Nerve Growth Factor

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Annu. Rev. Neurosci. 2001. 24:1217281

c 2001 by Annual Reviews. All rights reserved
Copyright
NERVE GROWTH FACTOR SIGNALING,

NEUROPROTECTION, AND NEURAL REPAIR
Annu. Rev. Neurosci. 2001.24:1217-1281. Downloaded from arjournals.annualreviews.org
by University of California - San Diego on 08/23/10. For personal use only.
Michael V Sofroniew
Department of Neurobiology and Brain Research Institute, University of California Los
Angeles, Los Angeles, California 90095-1763; e-mail: sofroniew@mednet.ucla.edu
Charles L Howe
Department of Neurology and Neurological Sciences, Stanford University, Stanford,
California 94305-5489; e-mail: c.howe@stanford.edu
William C Mobley
Department of Neurology and Neurological Sciences, Stanford University, Stanford,
California 94305; e-mail: ngfv1@leland.stanford.edu
Key Words neurotrophins, NGF, TrkA, p75NTR, neurodegeneration,

neuroregeneration, excitotoxicity, tyrosine kinase
Abstract Nerve growth factor (NGF) was discovered 50 years ago as a molecule
that promoted the survival and differentiation of sensory and sympathetic neurons. Its
roles in neural development have been characterized extensively, but recent findings
point to an unexpected diversity of NGF actions and indicate that developmental effects
are only one aspect of the biology of NGF. This article considers expanded roles for
NGF that are associated with the dynamically regulated production of NGF and its
receptors that begins in development, extends throughout adult life and aging, and
involves a surprising variety of neurons, glia, and nonneural cells. Particular attention
is given to a growing body of evidence that suggests that among other roles, endogenous
NGF signaling subserves neuroprotective and repair functions. The analysis points to
many interesting unanswered questions and to the potential for continuing research on
NGF to substantially enhance our understanding of the mechanisms and treatment of
neurological disorders.
INTRODUCTION
In mammals and other vertebrates, soluble peptide growth factors play essential
roles in intercellular communication. They exert their effects by signaling through
surface membrane receptors that interact with diverse types of intracellular secondmessenger systems. In a sometimes surprising manner, many growth factors have
been found to subserve a wide variety of functions by acting on many cell types
at different stages of development or in adult life.
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Nerve growth factor (NGF) was discovered 50 years ago as a molecule that regulates the survival and maturation of developing neurons in the peripheral nervous
system (PNS) (Levi-Montalcini & Hamburger 1951, 1953), and ideas about the
biological role of NGF have been dominated by concepts that arose from studies
on the differentiation and survival of young neurons. Until recently, the expectation was that the biology of NGF would center around the classical target-derived
neurotrophic factor paradigm in which NGF released by postsynaptic targets acts
on presynaptic neurons to build or maintain functional contacts and enhance the
function of well-defined neural circuits. Although this paradigm undoubtedly plays
a critical role in both the PNS and central nervous system (CNS), it does not appear to be the sole role for NGF actions. With the availability of tools that allow
sensitive and specific measurements of mRNA and protein levels for NGF and its
receptors, it has become apparent that NGF actions extend beyond the developmental period, beyond nerve cells, and even beyond the nervous system. Indeed,
NGF and its receptors are produced throughout adult life and during aging by
many different cell types. The dynamically regulated expression of NGF and its
receptors throughout adult life suggests multiple functions for NGF signaling,
many of which are poorly understood. NGF and NGF receptor expression can be
upregulated during the response to injury in both the PNS and CNS, and a growing body of evidence suggests that among other roles, endogenous NGF signaling
through both neurons and nonneuronal cells subserves neuroprotective functions
and facilitates neural repair.
One of the major advances of molecular neuroscience in the past 25 years has
been to recognize that much of the cellular damage resulting from such CNS
insults as stroke, trauma, and degenerative disease may be caused by a limited number of endogenously generated molecules with neurotoxic activities. Less
well developed is the idea that endogenous mechanisms exist to provide neuroprotection, and that endogenous molecules may be produced specifically to subserve
neuroprotective signaling functions (Mattson 1997). For NGF to be viewed as a
specifically expressed, neuroprotective molecule with widespread activity in the
CNS, several criteria must be fulfilled: (a) NGF and NGF receptor expression
must occur in cellular compartments where it could influence the neural response
to injury; (b) NGF signaling should be able to influence cellular events involved
in the response to insults and injury; (c) NGF should exert protective effects; and
(d) failure of NGF signaling should be associated with increased degeneration
and vulnerability to injury. In this review, we consider evidence supporting these
criteria and conclude that NGF does play a role in endogenous neuroprotection.
STRUCTURE, EXPRESSION, AND REGULATION

OF NGF AND ITS RECEPTORS
The NGF gene is located on human chromosome 1 and is expressed as two major
splice variants (Edwards et al 1986, 1988). The mature, fully processed form of
biologically active NGF appears to be similar in all tissues and consists of a dimer of
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13-kDa polypeptide chains, each of which has three intrachain disulfide bridges.
The crystal structure of NGF has been resolved (McDonald et al 1991). The NGF
dimer has an elongated shape with a core, or waist, that is formed by twisted beta
sheets; the molecule also features a cysteine-knot motif, a reverse turn at one end
(loop 3) and three beta-hairpin loops at the other (loops 1, 2, and 3). The amino
terminus of NGF is not defined in the crystal structure. An octapeptide derived from
the NGF amino terminus has potent bradykinin-like activity (Taiwo et al 1991)
and is normally produced in the mouse submandibular gland in response to stress,
but whether it is found under physiological conditions in other tissues is unknown
(Fahnestock et al 1991). NGF is part of the neurotrophin family of molecules, which
share a high degree of structural homology and includes brain-derived neurotrophic
factors (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) (Butte et al
1998; Ibanez 1994; Robinson et al 1995, 1999). Neurotrophins are found in both
mammals and lower vertebrates, and the neurotrophin homologues NT-6 and NT-7
were recently cloned in fish (Gotz et al 1994, Lai et al 1998).
NGF has two known receptors, TrkA and p75NTR (Bothwell 1995, Kaplan &
Miller 1997). TrkA is a single-pass transmembrane protein that serves as a receptor
tyrosine kinase (RTK) for NGF. NGF signaling through TrkA elicits many of the
classical neurotrophic actions ascribed to NGF (Loeb et al 1991). TrkA is a member
of the Trk gene family, which includes TrkB, the receptor for BDNF and NT-4, and
TrkC, the receptor for NT-3 (Kaplan & Miller 1997). NGF activates only TrkA;
NT-3 activates TrkA but only does so at much higher concentrations than does NGF.
Two isoforms for TrkA exist that differ in their extracellular domain through the
inclusion of six additional amino acids near the transmembrane domain of one of
the variants (TrkAII). Inclusion of the insert appears to relax the specificity of TrkA
activation; NT-3 mediated signaling is markedly enhanced through this receptor
isoform (Clary & Reichardt 1994). p75NTR is a transmembrane glycoprotein that
binds all members of the neurotrophin family with approximately equal nanomolar
affinity. p75NTR regulates signaling through TrkA; in addition, as discussed below,
NGF binding to p75NTR activates signaling pathways that are characteristic for this
receptor (Casaccia-Bonnefil et al 1999; Dobrowsky et al 1994, 1995; Friedman &
Greene 1999).
Recent findings for the three-dimensional structure of NGF bound to its TrkA
receptor provide a structural explanation for many of the results provided by mutagenesis studies (Wiesmann et al 1999). They show that NGF engages the TrkA
second immunoglobulin (Ig)-like domain through two distinct patches (Wiesmann
et al 1999). The first patch involves the four beta sheets that form the waist of the
NGF molecule together with the first loop (residues 2933); it includes NGF domains that show considerable homology with the other neurotrophins (Wiesmann
et al 1999). It is likely that NGF and its neurotrophin family members engage each
of their Trk receptors through this patch. The second patch is formed by the amino
terminus of NGF, which in the NGF-TrkA structure is well defined (Wiesmann
et al 1999). The lack of homology of the NGF amino terminus with that of other
neurotrophins suggests that the second patch serves to specify NGF binding to
TrkA. As yet there is no three-dimensional structure for NGF binding to p75NTR.
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Mutagenesis studies for NGF binding to p75NTR point to the importance of mostly
different domains (i.e. the first, third, and fourth loops and the carboxy-terminus)
(Ibanez et al 1992, Ryden & Ibanez 1997, Urfer et al 1994) than those identified
for binding to TrkA. The findings suggest that NGF could bind to both TrkA and
p75NTR simultaneously (Wiesmann et al 1999).
Both NGF and its receptors are produced during development, adult life, and
aging by many cell types in the CNS and PNS, immune and inflammatory system, and various tissues. Given the wide range of neuronal and nonneuronal cells
that have the potential to produce and/or respond to NGF, clues to the different
functions that might be played by NGF signaling have been obtained by examining the expression of NGF and its receptors. During development, expression
of NGF by target cells is compatible with its role as a survival and maturation
factor for afferent neurons. In addition, as discussed in this section, a large body
of evidence demonstrates that in response to numerous stimuli there is dynamic
regulation of NGF and NGF receptor expression. It is interesting that NGF and/or
its receptors are markedly upregulated by many cell types after tissue injury or
insult. Documenting the patterns for NGF and NGF receptor gene expression in
specific cells and tissues is required for documenting the plurality of NGF actions
and for interpreting their physiological significance.
Peripheral Nervous System and Peripheral Tissues

NGF Receptor Expressing Cells Sympathetic neurons and small diameter peripheral sensory neurons that mediate nociception, the first identified NGF-responsive neurons, express both TrkA and p75NTR during development and in the adult
(Ruit et al 1990, Verge et al 1989). Most, if not all, -motor neurons, whose cell
bodies reside in the CNS and send projections through peripheral nerve to muscle
targets, transiently express p75NTR during the phase of axon elongation that occurs
in development; expression is downregulated to undetectable levels in adults but
returns after peripheral nerve injury (Ernfors et al 1989, Wood et al 1990). Among
PNS glial cells, Schwann cells in peripheral nerve express p75NTR during development. In the normal adult, p75NTR expression is reduced to levels that are only
one percent of those seen during development (Heumann et al 1987b). Schwann
cells markedly upregulate p75NTR in response to the loss of contact with axons
that follows axotomy, to local tissue injury, or if stimulated with inflammatory
cytokines (Heumann et al 1987b, Lemke & Chao 1988, Mirsky & Jessen 1999,
Taniuchi et al 1988). Expression patterns for NGF receptors in the PNS suggest
that distinct functions are carried out during development, normal adult life, and
following injury.
NGF-Producing Cells Nonneuronal target cells of sympathetic and sensory neurons throughout the body produce NGF during development. These include targets
in the skin (e.g. keratinocytes and melanocytes), vascular and other smooth muscle
cells, and various endocrine tissues, such as the testis and ovary, pituitary, thyroid
and parathyroid, and exocrine salivary (e.g. submandibular) glands. Most of these
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cells continue to produce NGF during adult life and modulate NGF production
in response to stimuli (reviewed by Levi-Montalcini et al 1995, 1996). In some
tissues, including skin and viscera such as the bladder, experimental evidence suggests that NGF production is markedly upregulated after injury or in response to
tissue inflammation or injury, but the NGF-producing cell types have not yet been
characterized (Dmitrieva et al 1997, McMahon et al 1995, Mendell et al 1999).
Among PNS glia, immature Schwann cells and satellite cells produce NGF during development (Mirsky & Jessen 1999). In adults, mature myelinating Schwann
cells downregulate NGF expression to undetectable levels, but after nerve injury,
reactive and dedifferentiated Schwann cells markedly upregulate NGF production
in vivo; in vitro, NGF expression by Schwann cells is upregulated by cytokines and
other inflammatory mediators (Lindholm et al 1987, Mirsky & Jessen 1999). As
for its receptors, the patterns for NGF expression suggest roles that extend beyond development and beyond its classical role as a target-derived neurotrophic
factor.
Central Nervous System

NGF Receptor Expressing Cells p75NTR gene expression in the CNS is widespread, especially during development. In addition to both major populations of
forebrain cholinergic neurons, p75NTR mRNA and protein are found in a number of developing neuronal populations in both the brain and brainstem (Longo
et al 1993). p75NTR expression is more restricted in the adult, and several populations, including cholinergic neurons of the caudate-putamen and cranial nerve
nuclei of the brainstem, show markedly reduced or no expression (Koh & Higgins
1991). Cerebellar Purkinje neurons, hippocampal pyramidal neurons, and retinal
ganglion neurons also downregulate expression to undetectable levels in adults
but reexpress p75NTR after injury (Brann et al 1999, Eckenstein 1988, MartnezMurillo et al 1998, Yamashita et al 1999b). The majority of p75NTR-expressing
neurons do not also express TrkA, but developing horizontal cells and amacrine
cells of the retina express TrkA and potentially p75NTR (Karlsson et al 1998),
whereas cholinergic neurons of the septal-basal forebrain complex express both
TrkA and p75NTR during development and throughout adult life (Holtzman et al
1992). It is interesting that expression of TrkA, but not of p75NTR, in these neurons
is significantly decreased in aged animals (Cooper et al 1994, Hasenohrl et al 1997)
and is particularly reduced in aged patients with Alzheimers disease (Mufson et al
1997). Expression of both TrkA and p75NTR in forebrain neurons is upregulated
by NGF (Gage et al 1989, Holtzman et al 1992). Adult cholinergic neurons of
the extended striatal complex (caudate, putamen, accumbens, etc) express only
TrkA; however, p75NTR is upregulated to detectable levels, and TrkA expression
is increased by local tissue injury or NGF infusions (Gage et al 1989, Holtzman
et al 1995). Adult neurons that express TrkA, but not p75NTR, are found in the
thalamic paraventricular nuclei, rostral and intermediate subnuclei of the interpeduncular nucleus, and various other brain regions (Holtzman et al 1995, Venero
et al 1994), and also in the spinal cord in regions associated with regulation of the
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autonomic outflow (Michael et al 1997). TrkA mRNA has been detected in CNS
regions where its cellular localization is yet to be established. Some hippocampal
pyramidal neurons may also express very low levels of TrkA (Cellerino 1995), and
a recent immunocytochemical study points to the presence of TrkA and p75NTR
proteins in pyramidal cells of the somatosensory cortex of the mature rat (Pitts &
Miller 2000). If confirmed, these results would contribute significantly to our understanding of NGF production and actions in the CNS. As detection methods
increase in sensitivity, it is likely that other NGF receptor-expressing neurons will
be identified in the CNS.
Among glial cells, light microscopic studies show that CNS astrocytes in vivo
rarely stain for p75NTR (P Belichenko & WC Mobley, unpublished observations).
However, as many as one fifth of astrocytes in the dentate gyrus were immunoreactive for p75NTR in a recent immuno-EM study (Dougherty & Milner 1999).
This result suggests that very low levels of p75NTR are present in many mature
astrocytes. p75NTR and, more controversially, TrkA are also expressed by astrocytes
in vitro, particularly after exposure to NGF or inflammatory cytokines (Hutton et al
1992, Hutton & Perez-Polo 1995, Kumar et al 1993, Semkova & Krieglstein 1999).
A detailed analysis of NGF receptor expression by reactive astrocytes after CNS
injury would provide information for detailing the actions of neurotrophins in the
CNS. Astrocytes are not alone in expressing NGF receptors. Oligodendrocytes
express p75NTR (Casaccia-Bonnefil et al 1996, Kumar et al 1993). Microglia have
the capacity to express p75NTR and TrkA, and expression levels are modulated by
inflammatory stimuli, such as cytokines and bacterial lipopolysaccharide (Elkabes
et al 1998). The diversity of NGF receptor expression in the CNS is at least as
great as that in the PNS and suggests that NGF signaling mediates many different
functions.
NGF-Producing Cells NGF is produced in the CNS during development and
throughout adult life. NGF-producing cells are present in the cortical target regions
of basal forebrain cholinergic neurons. Most such cells are neurons, including pyramidal neurons, though glial cells are occasionally found to contain NGF (Pitts &
Miller 2000). In the hippocampal formation, pyramidal and dentate granule neurons express NGF, as do subpopulations of GABAergic interneurons (French et al
1999, Gall & Isackson 1989, Pascual et al 1998). These neurons also serve as
targets of cholinergic innervation. In striatum, NGF is produced by a subpopulation of small interneurons (Bizon et al 1999). NGF expression in hippocampus is
regulated by neuronal activity; increases are caused by glutamatergic and cholinergic neurotransmission, and decreases are caused by GABAergic neurotransmission
(Berzaghi et al 1993, Knipper et al 1994, French et al 1999). Neuronal NGF expression in vivo is markedly upregulated by seizures, forebrain ischemia, marked
hypoglycemia, and tissue injury (Gall & Isackson 1989, Lindvall et al 1994, Zafra
et al 1991). Studies in vivo and in vitro indicate that cerebral insults influence NGF
gene expression via excitatory amino acid neurotransmission as well as through
other pathways (Lindvall et al 1994).
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Among glial cells, NGF is produced throughout the CNS by astrocytes and
microglia, and NGF expression in both cell types is markedly upregulated by
local tissue injury, inflammation, cytokines, and bacterial lipopolysaccharide (both
in vivo and in vitro) (Arendt et al 1995, Elkabes et al 1996, Heese et al 1998,
Micera et al 1998, Yoshida & Gage 1992). In astrocytes, NGF expression is also
upregulated by fibroblast growth factor, interleukin-1, glutamate agonists, reactive
oxygen species, high potassium, ischemia, and traumatic brain injury (Abiru et al
1998; Friedman et al 1996; Goss et al 1998; Gottlieb & Matute 1999; Pechan
et al 1992, 1993; Strauss et al 1968; Yoshida & Gage 1991). The data for NGF
expression in the uninjured brain are largely consistent with a role for NGF in
target-derived trophic support. Increased NGF levels in the injured CNS suggest
that astrocytes and microglial cells could serve as local sources of NGF for injured
neurons and other NGF responsive cell types.
Immune and Inflammatory System

In recent years, a great deal of interest has focused on NGF and NGF receptor
gene expression in cells of the immune and inflammatory system. Several types
of bone marrow-derived leukocytes have the capacity to express TrkA, including
mast cells, CD4+ T lymphocytes, B lymphocytes, monocytes, and macrophages;
follicular dendritic cells and B lymphocytes express p75NTR (Labouyrie et al 1997,
Levi-Montalcini et al 1996, Torcia et al 1996). Many of the same types of leukocytes
also have the capacity to express NGF. These include mast cells, monocytes and
macrophages, T lymphocytes (CD3+ and CD4+ T cells), and B lymphocytes
(Lambiase et al 1997, Leon et al 1994, Levi-Montalcini et al 1996, Mizuma et al
1999, Torcia et al 1996). Both NGF and NGF receptor expression are dynamically
regulated in leukocytes such that expression is increased by inflammatory and
other stimuli as well as in activated cells (Barouch et al 2000, Lambiase et al 1997,
Levi-Montalcini et al 1996, Mizuma et al 1999, Torcia et al 1996). A previously
unexpected role for NGF in immune and inflammatory functions is suggested by
these findings.
NGF SIGNALING MECHANISMS

Cellular responses to NGF are elicited through binding and activation of its receptors, TrkA and p75NTR (Bothwell 1995). NGF signaling is now recognized
as being broad based, dynamically regulated, and context dependent. Numerous
intracellular signaling cascades are triggered by NGF receptor activation, and there
is evidence for convergence of, and direct interactions between, NGF signaling and
signaling triggered by other molecules. Studies on the intracellular signaling cascades triggered by NGF have relied heavily on in vitro models using primary cell
cultures or cell lines, in particular the rat pheochromocytoma cell line PC12. In
fact, many of the signaling cascades discussed in the following section have only
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been delineated in PC12 cells. However, the insights gained from analysis of such
cell culture models are useful in the context of an instructive role for further investigation of NGF signaling within neurons and other neural cells. Likewise, studies
of NGF signaling have largely focused on developmental processes, such as neuronal differentiation and neurite outgrowth, but information about NGF signaling
mechanisms in other contexts, such as degeneration, death, and neuroprotection is
increasingly available.

NGF Signaling Through TrkA

TrkA Activation TrkA, a single transmembrane-spanning polypeptide chain
member of the receptor tyrosine kinase (RTK) superfamily, was initially discovered as an oncogenic fusion protein isolated from human colon carcinoma
(Martin-Zanca et al 1986a,b). Genetic analysis revealed that in normal cells the
proto-oncogene encoded a 140-kDa glycosylated protein containing an extracellular region comprised of several immunoglobulin-like binding domains, a short,
single transmembrane domain, and an intracellular domain encoding a tyrosine
kinase (Martin-Zanca et al 1989). Following its initial discovery in 1986, the receptor remained an orphan receptor until 1991, when it was discovered that NGF
evoked a rapid tyrosine phosphorylation of endogenous TrkA in PC12 cells and
of exogenous TrkA in transfected fibroblasts (Kaplan et al 1991a,b; Klein et al
1991). Furthermore, TrkA was found to elicit signaling cascades necessary for the
biological responses of PC12 cells and neurons to NGF. Upon binding of NGF to
TrkA, the receptor is subjected to a series of events that characterize RTK signaling. These include receptor dimerization and transphosphorylation of activation
loop tyrosines leading to activation of kinase activity, followed by autophosphorylation of tyrosines outside of the activation loop (Cunningham et al 1997). These
autophosphorylation sites serve as binding sites for specific signaling proteins and
adaptors such as PLC and Shc. Subsequent phosphorylation and activation of
accessory proteins lead to the generation of a cascade of receptor-independent
signaling pathways (Greene & Kaplan 1995).
Ras Pathway Tyrosines 490 and 785 are two autophosphorylation targets that
are transphosphorylated following TrkA kinase activation (Loeb et al 1994,
Middlemas et al 1994, Stephens et al 1994). Shc, an adaptor protein that is critical to
activation of the Ras signaling cascade (Figure 1) binds to phosphorylated tyrosine
490 (Basu et al 1994, Obermeier et al 1994). Following binding and phosphorylation of Shc, the Grb2-Sos complex binds to phospho-Shc via an SH2 interaction
(Rozakis-Adcock et al 1992), thereby bringing Sos into proximity to membraneassociated Ras and activating the MAP kinase signaling cascade. Sos is a Ras
GTP exchange factor that promotes the transition from inactive Ras-GDP to active
Ras-GTP (McCormick 1994). Ras is targeted to the plasma membrane via farnesylation (Casey 1995) and resides at the plasma membrane in an inactive,
GDP-bound state. Upon recruitment of Sos to the membrane, Ras is activated by
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exchange of GDP for GTP (McCormick 1994). Ras then recruits the serinethreonine kinase C-Raf to the plasma membrane (Marshall 1994, Van Aelst et al
1993, Wood et al 1992). In PC12 cells, Raf family members (Jaiswal et al 1994,
Oshima et al 1991, Traverse & Cohen 1994) mediate NGF signaling by phosphorylating and thereby activating the dual-specificity MAP kinase kinase MEK1
at serine 217 and serine 221 (Jaiswal et al 1994, Lange-Carter & Johnson 1994,
Vaillancourt et al 1994). MEK1 activation leads to the phosphorylation of two
members of the MAP kinase family, extracellular signal-related kinases 1 and 2
(Erk 1/2) (Crews et al 1992, Crews & Erikson 1992). Erk1/2 are phosphorylated on
threonine 202 and tyrosine 204 by MEK1 (Payne et al 1991), leading to activation
and translocation of Erk1/2 into the nucleus (Chen et al 1992). Erk1/2 are prolinedirected serine-threonine kinases that phosphorylate several substrates, including
Elk-1 (Miranti et al 1995). Phosphorylation of Elk-1 at serine 383 and serine
389 stimulates its interaction with the transcription factor serum response factor
(SRF) and with the CAGGAT binding site of the serum response element (SRE)
within the c-fos gene (Gille et al 1995, Hill et al 1993, Mueller & Nordheim 1991,
Treisman 1992). c-fos is an immediate early gene that is rapidly transcribed in
response to many extracellular stimuli, including NGF, and is an early component
of a series of transcriptional events necessary for initiation and maintenance of
differentiation (Ginty et al 1994, Greenberg et al 1986, Sheng & Greenberg 1990).
Additional transcription factors contribute to the regulation of c-fos transcription in response to NGF signaling. The cAMP regulatory element binding protein
(CREB) is a transcription factor that binds to a site called the CRE, or cAMP
response element, within the c-fos promoter (Berkowitz et al 1989). NGF signaling leads to the phosphorylation of CREB at serine 133 via a Ras-dependent
mechanism (Ginty et al 1994). This allows CREB to interact with SRF and Elk-1
(Bonni et al 1995, Ramirez et al 1997), possibly via the transcriptional coactivator
protein CREB binding protein (CBP), which binds to phosphorylated serine 133
in CREB (Chrivia et al 1993). CBP also binds to SRF (Ramirez et al 1997) and
Elk-1 family members (Janknecht et al 1993). CREB may also play an important role in transcriptional regulation of several NGF-specific delayed response
genes, including the VGF gene. Mutation of the CREB binding site within the
VGF gene significantly reduced NGF-induced VGF transcription (Hawley et al
1992). It is interesting that VGF transcription may require the cooperation of
CREB with an as yet unidentified transcription factor product of an immediate
early gene. CREB is persistantly phosphorylated at serine 133 for several hours
after an initial NGF stimulus, and this may permit accumulated immediate early
gene proteins to interact with activated CREB. In contrast, EGF stimulation, which
does not lead to VGF transcription, only transiently phosphorylates CREB, such
that by the time sufficient immediate early gene product is present, activated CREB
may no longer be available to cooperatively stimulate VGF transcription (Bonni
et al 1995). This may be one mechanism by which NGF and EGF activate different
transcriptional programs leading to either differentiation or proliferation (Marshall
1994).
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Map Kinase Temporal Dynamics The difference in temporal control of CREB

phosphorylation induced by NGF or EGF is a specific example of a more general temporal difference elicited in the MAP kinase pathway by these two growth
factors. In PC12 cells treated with NGF, there is a sustained activation of the MAP
kinase pathway that persists for several hours. In contrast, EGF stimulation only
transiently activates the MAP kinase pathway (Muroya et al 1992, Qui & Green
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1992, Traverse et al 1992), suggesting that the temporal dynamics of Erk1/2 activation may account for a differentiative versus proliferative signaling outcome.
One explanation for how two RTKs linked to very similar signaling pathways
might induce such very different MAP kinase activation kinetics requires a better understanding of the specific isoforms of certain adaptor proteins utilized in
these cascades. For example, while both NGF and EGF appear to utilize the classic Shc/Grb2/Sos/Ras/C-Raf/MEK pathway to activate Erk, NGF also utilizes an
accessory route to Erk activation that utilizes Gab2/CrkL/C3G/Rap1/B-Raf/MEK
(Figure 1). This second pathway, which may be unique to NGF signaling, promotes sustained activation of Erk1/2 (CB Wu, CF Lai, WC Mobley, submitted
for publication; York et al 1998). The persistant Erk activation that follows NGF
stimulation of the Rap1 pathway may induce expression of immediate early gene
proteins that interact with activated CREB, induce transcription of novel delayed
response genes, or both. Rap1 signaling through MAP kinase does not regulate
all aspects of differentiation, nor can one exclude a role for Ras. Expression of
a mutant Rap that blocks sustained Erk activation in response to NGF does not
block neurite outgrowth in PC12 cells (York et al 1998). On the other hand, complete inhibition of Erk activation, either by pharmacological inhibition of MEK or
transfection with a dominant-interfering MEK mutant, does block NGF-induced
neurite outgrowth (Cowley et al 1994, Pang et al 1995), and inhibition of Ras activity by microinjection of a Ras-neutralizing antibody also blocks differentiation
(Hagag et al 1986). Thus, Ras-dependent signaling is apparently important for
NGF-induced differentiation. It is likely that some early event triggered by a Rasand C-Raf-mediated activation of the Erk pathway is necessary for priming the
cell to respond to the later and sustained activation of Erk by the Rap1 and B-Raf
pathway.
Figure 1 The Ras-MAP kinase cascade downstream from TrkA. Following phosphorylation
of tyrosine 490 within TrkA, Shc is recruited to the receptor via either an SH2- or phosphotyrosinebinding domain-based interaction. Consequently, Shc is bound by the Grb2-Sos complex. Recruitment of Sos to the membrane brings it into proximity of Ras, where it functions as a GTP-exchange
factor, activating Ras. Activated Ras recruits and activates Raf. Raf is a serine-threonine kinase
that phosphorylates the MAP kinase kinase MEK on 2 serines. This phosphorylation event initiates
activity of the dual-specificity kinase, leading to activation of the MAP kinases Erk1/2 via phosphorylation of threonine 202 and tyrosine 204. Phosphorylated Erk1/2 then participate in at least
two cascades. Erk1/2 may translocate into the nucleus, where they phosphorylate the transcription
factor Elk-1, or they may phosphorylate the kinase Rsk. Phosphorylation of Elk-1 allows it to
interact with the accessory transcription factor SRF, after which it binds to the serum response
element (SRE) within the c-fos promoter region and contributes to initiation of transcription. Phosphorylation of Rsk leads to its nuclear translocation and consequent phosphorylation of CREB on
serine 133. Phosphorylated CREB is bound by the transcriptional coactivator protein CPB, which
also binds to the SRF-Elk complex, creating an extended transcriptional factor complex that leads
to c-fos transcription.
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Rsk Pathway A further level of control of NGF-induced immediate early gene

transcription and translation comes from parallel activation of the Rsk pathway
downstream from Ras. The Rsk serine-threonine kinase was originally isolated as
a 90-kDa cell-cycle regulated kinase that phosphorylated the S6 protein of the 40S
ribosomal subunit (Erikson & Maller 1991, Erikson et al 1991). This p90 kinase
(ribosomal S6 kinase, hence Rsk) was itself found to be regulated by serinethreonine phosphorylation, and Erk1/2 were subsequently identified as the kinases
responsible for this regulatory phosphorylation (Sturgill et al 1988, Zhao et al
1996). The Rsk family is comprised of Rsk1, Rsk2, and Rsk3, each showing unique
patterns of tissue expression (Moller et al 1994, Zhao et al 1995). Rsk2 was identified as a Ras-dependent protein kinase that phosphorylates CREB on serine 133
(Ginty et al 1994, Xing et al 1996), thereby regulating its transcriptional activation.
Rsk family members are also involved in phosphorylation of the estrogen receptor, IB/NFB, and c-fos (Ghoda et al 1997, Joel et al 1998, Schouten et al 1997,
Xing et al 1996). Rsks also bind to the transcriptional coactivator CBP (Nakajima
et al 1996) and phosphorylate several members of the ribosomal complex
(Angenstein et al 1998). Sos, a substrate for Rsk, appears to be negatively regulated by Rsk kinase activity, suggesting that Rsk activation downstream from activation of Erk1/2 may feed back to truncate Ras signaling (Douville & Downward
1997). Recently, all three members of the Rsk family were found to be activated
by NGF in PC12 cells, and all were able to phosphorylate CREB at serine 133
(Xing et al 1998). Hence, the Ras pathway is able to regulate c-fos induction by
using a parallel and cooperative pathway in which Erk phosphorylation of Elk-1
converges upon Rsk phosphorylation of CREB (Xing et al 1996). Thus, the Erk
pathway is marked by both divergent and convergent signaling, in which an early
divergence at the level of Shc versus Gab2 can control the temporal dynamics of
Erk activation, and convergence at the level of Elk-1 and CREB regulation of c-fos
can control gene transcription and protein translation.
Src and PKC Pathways Convergence of control over the MAP kinase pathway
may also occur between Ras, PKC, and Src. Src is a member of a large family
of nonreceptor protein tyrosine kinases that share significant sequence homology.
This family includes Fyn, Yes, Yrk, Blk, Fgr, Hck, Lck, Lyn, Frk/Rak, and Iyk/Bsk
(Brown & Cooper 1996, Cance et al 1994, Lee et al 1994a, Thomas & Brugge
1997, Thuveson et al 1995, Welch & Maridonneau-Parini 1997). Src kinases regulate a wide range of cellular events, ranging from cell proliferation, cytoskeletal
alterations, and differentiation, to survival, adhesion, and migration. RTKs interact
with Src kinases and use them to transduce several signaling pathways (Erpel &
Courtneidge 1995). Involvement of Src or an Src family member in NGF-mediated
differentiative signaling was first proposed when it was discovered that infection
of PC12 cells with the oncogenic form of Src recapitulated the neurite outgrowth
induced by NGF (Alema et al 1985). Further analysis showed that neutralization
of Ras by microinjection of anti-Ras antibodies blocked the neuritogenic effects of
both Src and NGF (Hagag et al 1986, Kremer et al 1991). In contrast, neutralization
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of Src activity by antibody microinjection did not block neurite outgrowth induced
by infection with oncogenic Ras (Bar-Sagi & Feramisco 1985, Kremer et al 1991,
Noda et al 1985) but did inhibit NGF-induced neuritogenesis. It also caused retraction of established neurites induced by NGF or FGF treatment (Kremer et al
1991). Finally, both oncogenic Src and oncogenic Ras are able to prime PC12
cells, such that subsequent NGF treatment elicits a more rapid and robust neuritogenesis than NGF treatment of unprimed cells (Thomas et al 1991). It is interesting
that oncogenic Src activated the N-terminal c-jun kinase (JNK), a member of the
MAP kinase family, without activating Erk1/2 (Kuo et al 1997). Hence, one possible explanation for the role that both Src and Ras play in differentiation is that
they control the activity of a common MEK family member that is upstream of
both Erk1/2 and JNK (Ellinger-Ziegelbauer et al 1997, Lewis et al 1998). This
model is compatible with data showing that pharmacological inhibition of MEK
in PC12 cells abrogated neurite outgrowth in response to NGF (Pang et al 1995).
MEK activity is also regulated by several PKC isoforms (Berra et al 1993, 1995;
Schonwasser et al 1998, van Dijk et al 1997), and overexpression of either PKC or
PKC resulted in enhanced NGF-induced neurite outgrowth and enhanced NGFinduced JNK activation (Wooten et al 1999), while inhibition of atypical PKC
isoforms blocked NGF-induced activation of JNK (Wooten et al 1999). PI3 kinase is also implicated in signaling to JNK, as NGF-induced JNK activation was
impaired by either wortmannin or LY294002, and overexpression of PI3 kinase
resulted in neurite outgrowth and JNK activation in the absence of Erk activation
(Kobayashi et al 1997). Thus, a signaling cascade including Src, PI3 kinase, PKC,
and JNK appears to be involved in neurite outgrowth and differentiative signaling
and may either complement or parallel the Ras-Raf-MEK-Erk1/2 cascade.
Signaling through Src, PI3 kinase, PKC, and JNK may also play a role in cell
survival signaling. Overexpression of either Src or PKC enhanced PC12 cell survival in serum-free conditions, and both increased the activation of the transcription
factor NFB (Wooten et al 2000, 1999), apparently via JNK signaling. Moreover,
inhibition of Src or atypical PKC isoforms promoted cell death (Seibenhener et al
1999, Wooten et al 2000). Likewise, inhibition of PI3 kinase activity blocked cell
survival and reduced NGF-induced NFB activation (Wooten et al 2000). These
findings are compatible with data showing that activation of NFB promotes cell
survival and resistance to apoptosis, and that NGF induction of NFB is primarily
dependent on signaling through the JNK pathway (Wooten et al 2000). Thus, both
differentiative and survival signaling may be controlled in part by a signaling unit
that includes Src, PI3 kinase, and PKC.
PI3 Kinase Pathway PI3 kinase and Src are also implicated in survival signaling via the common substrate Akt, a serine-threonine kinase also known as protein
kinase B (PKB), or related to A and C protein kinase (RAC-PK). Akt is regulated
by growth factor and serum factor signaling through PI3 kinase (Alessi et al 1996;
Andjelkovic et al 1996; Burgering & Coffer 1995; Franke et al 1995, 1997; Klippel
et al 1997). PI3 kinase is a heterodimer composed of an 85-kDa regulatory subunit
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and a 110-kDa catalytic subunit. Activation of the kinase involves binding of the
regulatory subunit either directly or via adaptors to activated RTKs. This interaction with the cytoplasmic domain of an RTK results in recruitment of the 110-kDa
catalytic subunit to the plasma membrane, where it can interact with and phosphorylate membrane phosphoinositides. Such phosphorylation results in the production of PI-3,4-P2 and PI-3,4,5-P3. Akt interacts with PI-3,4-P2 or PI-3,4,5-P3,
and with the 3-phosphoinositide-dependent kinase (PDK1). PDK1 contains a
pleckstrin homology domain that binds PI-3,4-P2 or PI-3,4,5-P3, and this binding is necessary to permit PDK1 to phosphorylate and activate Akt (Alessi et al
1997a,b; Cohen et al 1997; Stephens et al 1998; Stokoe et al 1997). Hence, TrkA
signaling via PI3 kinase presumably signals to generate 3-phosphoinositides that
bind PDK1 and induce the activation of Akt. PDK1 phosphorylates the activation loop of several other serine-threonine kinases, including certain isoforms of
PKC (Chou et al 1998, Le Good et al 1998), suggesting that PI3 kinase-mediated
generation of 3-phosphoinositides may also control differentiative or survival signaling via PKC activation.
Mediation of TrkA survival signaling by PI3 kinase is indicated by the results
of experiments showing that two inhibitors of PI3 kinase activity, wortmannin and
LY294002, induce apoptosis in PC12 cells and sympathetic neurons supported
by NGF (Crowder & Freeman 1998, Yao & Cooper 1995). The role of Akt in
regulation of cell survival downstream from PI3 kinase is suggested by the fact
that overexpression of Akt in primary cultures of cerebellar neurons or sympathetic neurons provides protection against death induced by serum withdrawal or
inhibition of PI3 kinase, while expression of dominant-interfering forms of Akt
blocked NGF-mediated survival (Crowder & Freeman 1998, Dudek et al 1997).
The mechanism by which Akt mediates survival is unclear, though Akt has been
reported to bind and phosphorylate Bad, a member of the Bcl-2 family of proteins
(Figure 2) (Datta et al 1997, del Peso et al 1997). Phosphorylation of Bad prevents
it from binding the anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-XL (Zha
et al 1996), shifting the cell to contain more Bcl-2 homodimers than Bcl-2/Bax
heterodimers. The Bcl family is composed of two groups of proteins, one that
promotes cell survival and includes Bcl-2 and Bcl-XL, and the other that promotes
cell death and includes Bad and Bax (Boise et al 1995, Kroemer 1997, Steller
1995). The members of the Bcl family form homo- and heterodimers, and the
balance of each dimer within the cell is considered to regulate the maintenance
of survival or the induction of death. In the absence of phosphorylation of Bad
on serine 112 and serine 136, Bad signals to promote cell death, apparently by
forming heterodimers with Bcl-XL. Formation of these heterodimers leads to the
generation of Bax homodimers. Homodimerization of Bax induces its translocation into mitochondria and insertion into the mitochondrial membrane (Gross et al
1998). There it leads to altered mitochondrial membrane potential via ion channel formation and to generation of cytotoxic reactive oxygen species (Xiang et al
1996). In contrast, the phosphorylation of Bad promotes cell survival by inducing
an interaction between Bad and the 14-3-3 protein. This interaction effectively
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Figure 2 TrkA survival signaling TrkA phosphorylation leads to the activation of PI3 kinase.
PI3 kinase catalyzes the production of 3-phosphoinositides, including PI-3,4,5-P3, which bind to
and activate PDK1. PDK1 associates with and phosphorylates the serine-threonine kinase Akt. Akt
then phosphorylates Bad, inducing its association with the 14-3-3 protein and sequestering it from
heterodimerization with Bcl-XL. As a result of Bad sequesteration, Bcl-XL is able to heterodimerize
with Bax, preventing Bax homodimerization. Homodimerized Bax is a key element in apoptotic
signaling, via its role in altering mitochondrial membrane potential, and the balance of Bax:Bax
homodimers versus Bax:Bcl-XL heterodimers may determine whether the cell lives or dies.
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sequesters Bad from any interaction with Bcl-XL, keeping the balance of BclXL/Bax heterodimers high and preventing Bax homodimerization (Zha et al 1996).
Hence, TrkA survival signaling involves PI3 kinase-mediated activation of Akt and
the consequent maintenance of Bcl-XL/Bax heterodimers. Src is also implicated in
the activation of Akt via a mechanism that involves PI3 kinase and SHP-2 (Datta
et al 1996, Hakak et al 2000). This interaction may explain the finding, presented
above, that inhibition of Src promotes cell death, and it suggests that additional
complexity may exist in the mechanism by which TrkA signaling induces cell
survival.
TrkA activation may be linked to the phosphotidylinositol 3-kinase (PI3 kinase)
pathway via binding of Grb2 and the Grb2-associated binder-1 (Gab1) protein to
tyrosine 490. Gab1 was initially identified as a Grb2-associated protein in a human
glial tumor expression library and was also identified in a yeast 2-hybrid screen
using the Met RTK as bait (Holgado-Madruga et al 1996, Weidner et al 1996).
Gab1 is a member of a family of adaptor proteins that includes Gab2, IRS-1,
IRS-2, and Dos, all of which exhibit sequence homology, and all of which link
plasma membrane RTKs to intracellular signaling cascades (Bausenwein et al
2000, Gu et al 1998). Gab1 contains several SH2 and SH3 binding domains that
recognize PI3 kinase and SHP-2, as well as Grb2, Nck, and Crk (Holgado-Madruga
et al 1996, Weidner et al 1996). Gab1 is tyrosine phosphorylated in response to
signaling downstream from TrkA (Holgado-Madruga et al 1997), and it is also
induced to associate with PI3 kinase, recruiting the p85 subunit to the plasma
membrane and eliciting activation. Furthermore, overexpression of Gab1 reduced
the concentration of NGF necessary for mediating cell survival in serum-free
conditions, while expression of a mutant Gab1 lacking the PI3 kinase binding
sites enhanced apoptosis (Holgado-Madruga et al 1997). These data suggest that
anti-apoptotic TrkA signaling to PI3 kinase and the Akt pathway is mediated by
Gab1. This is supported by the finding that adenovirus-mediated expression of
Gab1 in PC12 cells is sufficient to support enhanced survival, even in the absence
of NGF signaling, and that this enhancement is correlated with increased PI3
kinase signaling (Korhonen et al 1999). However, Gab1 appears to utilize both
the PI3 kinase pathway and the MAP kinase pathway to mediate its effect on cell
survival, as pharmacological inhibition of both MEK and PI3 kinase was required
to fully suppress Gab1-mediated cell survival (Korhonen et al 1999). Finally,
adenovirus-expressed Gab1 enhanced neurite outgrowth in response to NGF via
a mechanism that was sensitive to either MEK inhibition or PI3 kinase inhibition
(Korhonen et al 1999). These results suggest that Gab1 plays a role as an adaptor
protein for both the PI3 kinase pathway and the MAP kinase pathway downstream
from TrkA signaling. However, another member of the Gab family, Gab2, was
recently identified as a substrate for tyrosine phosphorylation downstream of TrkA,
and Gab2 was found in complex with CrkL, C3G, and SHP-2 following NGF
treatment of PC12 cells (CB Wu, CF Lai, WC Mobley, submitted for publication).
This finding suggests that Gab2 may adapt TrkA to the Rap1/B-Raf pathway by
inducing NGF-dependent activation of C3G, a Rap GTP exchange factor. In that
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activation of the Rap1 pathway leads to MEK activation in parallel with the Ras
pathway, as described above, it is possible that overexpressed Gab1 subsumes the
role of endogenous Gab2 in mediation of neurite outgrowth.
FRS-2 In addition to binding Shc and Gab, tyrosine 490 also appears to mediate
the interaction of TrkA with FRS-2, a novel membrane-anchored adaptor protein
that is tyrosine phosphorylated in response to NGF (Kouhara et al 1997, Ong
et al 2000). Phosphorylated FRS-2 binds to the Grb2-Sos signaling unit, forming
a multi-protein complex that includes Crk and the protein tyrosine phosphatase
SHP-2 (Hadari et al 1998, Kouhara et al 1997, Meakin et al 1999). Formation of
this complex is necessary for FRS-2 activation of the MAP kinase pathway. FRS-2
competes with Shc for binding to tyrosine 490 on TrkA, adding an interesting
layer of complexity to the signaling cascades elicited by NGF treatment (Meakin
et al 1999). FRS-2 may or may not be identical to SNT (Friedman & Greene 1999,
Kouhara et al 1997), a protein that may be a candidate for the factor that controls the
decision between cell-cycle progression and cell-cycle arrest, a critical component
of differentiative signaling. The ability of SNT to bind the cyclin-dependent kinase
substrate p13suc1, and the fact that it is rapidly tyrosine phosphorylated in response
to NGF (Rabin et al 1993) suggests that SNT may be the mediator of this key
decision. While the relationship between SNT and FRS-2 is still unresolved, recent
evidence indicates that human FRS-2 does bind p13suc1 in a constituitive manner
(Meakin et al 1999), strengthening the possibility that FRS-2 is an SNT.
It is interesting to note that mutations in tyrosine 490 of TrkA do not abolish
NGF induction of the MAP kinase signaling pathway. However, cells expressing
TrkA with a double mutation at tyrosine 490 and tyrosine 785 do not exhibit
MAP kinase activation or neurite outgrowth in response to NGF (Stephens et al
1994). This finding suggests that there is an as yet undiscovered complexity or
redundancy to the interaction of adaptor proteins with tyrosines 490 and 785. One
possible component in this additional complexity is the recent finding that Grb2
binds directly to activated TrkA at both tyrosine 785 and the kinase activation loop
tyrosines (MacDonald et al 2000). This additional route to the Ras pathway may
circumvent loss of either tyrosine 490 or tyrosine 785, but not both.
PLC and PKC Pathways Tyrosine 785, near the C terminus of TrkA, is within
a consensus site for the binding of the SH2 domain of phospholipase C- (PLC ).
This tyrosine is required for NGF-dependent recruitment of PLC to TrkA and
for the phosphorylation and activation of PLC (Vetter et al 1991). Following
binding to tyrosine 785 of TrkA, PLC is activated and induced to hydrolyze
phosphatidylinositol 4,5-bisphosphate (PI 4,5-P2). PLC -mediated hydrolysis of
PI 4,5-P2 yields two products that each function as intracellular second messengers:
inositol 1,4,5-P3 (IP3), which interacts with its specific receptor on the endoplasmic
reticulum to induce the release of intracellular calcium, and diacylglycerol (DAG),
which is a potent activator of protein kinase C (PKC) isoforms (Lee & Rhee 1995).
IP3-mediated release from intracellular calcium stores leads to the activation of
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calcium-dependent proteins within the cell and to the generation of further IP

derivatives such as IP4, IP5, and IP6, which are able to interact with other intracellular proteins (Menniti et al 1993). DAG is an activator of several isoforms of
the serine-threonine calcium-dependent kinase PKC. These include several classical, novel, and atypical PKC isoforms (Bell & Burns 1991; Nishizuka 1988;
Liyanage et al 1992; Ono et al 1988; Osada et al 1990, 1992; Marais et al
1998). DAG cooperates with calcium, phosphatidylserine, cis-unsaturated fatty
acids, and lysophosphatidylcholine to activate the classical PKC isoforms, and
it cooperates with phosphatidylserine and cis-unsaturated fatty acids to activate
the and isoforms of novel PKC. PLC activation is often accompanied by
phospholipase A2mediated hydrolysis of phosphatidylcholine, directly generating cis-unsaturated fatty acid and lysophosphatidylcholine (Asaoka et al 1992,
Nishizuka 1992). These factors, in combination with DAG, serve to tune PKC activation to signaling downstream from TrkA, leading to phosphorylation of several
proteins critical to survival and differentiation (Coleman & Wooten 1994; Wooten
et al 1994, 1997, 1999). One such substrate of PKC is Raf, which is directly activated by PKC-mediated phosphorylation (Carroll & May 1994, Kolch et al 1993,
Schonwasser et al 1998, Sozeri et al 1992, van Dijk et al 1997). The association of
PKC with Raf appears to be mediated by binding of the scaffolding protein 14-3-3
(Freed et al 1994, Fu et al 1994, Irie et al 1994, van der Hoeven et al 2000). A
PKC-(14-3-3)-Raf complex may also contribute to PKC - and PKC-mediated
regulation of the MAP kinase cascade (Hausser et al 1999, Meller et al 1996) and
may account for PKC-mediated activation of Raf (Cacace et al 1996, Ueffing et al
1997). PKC might also mediate activation of the MAP kinase cascade by directly
activating Ras, leading to the formation of a (Ras-GTP)-Raf complex (Marais et al
1998). This finding is consistent with evidence that PKC-mediated activation of
Raf is blocked by mutation in the Ras-binding domain of Raf (Luo et al 1997).
Finally, PKC can directly phosphorylate the c-jun protein product, which is also
under the control of phosphorylation by Erk and which is able to bind to the c-fos
protein product to form the transcriptional regulatory complex AP-1 (Oberwetter
et al 1993).
Abl Pathway The juxtamembrane region of TrkA, a unique region in the cytoplasmic domain of the receptor, has also been implicated in carrying out several
specific signaling functions downstream from NGF binding. This region apparently mediates the association of activated TrkA with Abl, a nonreceptor tyrosine
kinase that is involved in the regulation of adhesion-dependent signaling and cytoskeletal remodeling that occurs during neuronal differentiation (Yano et al 2000).
The association of Abl with TrkA may lead to its activation, and consequently to the
phosphorylation of paxillin (Matsuda et al 1994, Ribon & Saltiel 1996, Teng et al
1995, Torres & Bogenmann 1996). It is interesting to note that tyrosine phosphorylation of paxillin is critical to the increased cell adhesion necessary for neurite
outgrowth, and that Abl is involved in this pathway in Drosophila (Gertler et al
1989, 1993; Wills et al 1999).
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rAPS- and SH2-B-Mediated Pathways Two other adaptor proteins that do not
appear to interact with either tyrosine 490 or tyrosine 785 are rAPS and SH2-B,
which were recently identified as TrkA substrates in developing cortical and sympathetic neurons (Qian et al 1998). Both rAPS and SH2-B were found in complex
with Grb2, and either adaptor was able to mediate NGF induction of MAP kinase
activation. In nnr5 PC12 cells that express extremely low levels of TrkA, cotransfection with rAPS and a TrkA mutant lacking all tyrosines except those in the
kinase activation loop, or with SH2-B and this TrkA mutant, led to robust neurite
outgrowth (Qian et al 1998). Moreover, while the interaction between rAPS and
Grb2 is at least partially dependent on tyrosine phosphorylation of rAPS, Grb2
appears to bind to SH2-B constituitively via an SH3 interaction. Finally, antibodies
to SH2-B inhibited NGF-dependent survival of cultured neonatal sympathetic neurons, and transfection with a dominant-interfering mutant of SH2-B completely
blocked the elaboration of axons by cultured sympathetic neurons. This suggests
that SH2-B and rAPS are critical elements in the TrkA signaling pathway necessary for both neurite outgrowth and survival, but that their interaction with TrkA
may utilize a novel association mechanism.
NGF Signaling Through p75NTR

p75NTR was the first identified NGF receptor and for many years was believed to
be the only such receptor. However, following the discovery of a receptor tyrosine
kinase for NGF that exhibited readily identifiable signaling properties, p75NTR
was largely relegated to the role of modulating and modifying TrkA signaling.
While such a role continues to be an important area of investigation, it has become
increasingly clear that p75NTR is a signaling receptor in its own right. In fact, the
signals initiated by p75NTR are likely to be as complex as those for TrkA and to
be critically influenced by the cells in which such signaling arises (Friedman &
Greene 1999, Kaplan & Miller 1997). The function of NGF signaling via p75NTR
in the context of cell death and regeneration may be important for understanding
NGF actions in controlling the processes of neural repair and neuroprotection.
p75NTR is the first identified member of a superfamily of receptors that includes
CD27, CD30, CD40, OX40, Fas (CD95), and the tumor necrosis factor receptors
(TNF-R) (Bazan 1990, Cosman et al 1990, Mallett & Barclay 1991, Smith et al
1994). These receptors share several common signaling features, including the
ability to control cell viability via regulation of apoptosis. For example, in the
embryonic chick retina, neural precursor cells expressing p75NTR in the absence
of TrkA undergo NGF-dependent apoptosis, suggesting that developmentally programmed death in these cells is mediated by p75NTR (Bredesen & Rabizadeh
1997, Carter & Lewin 1997, Frade et al 1996). Furthermore, p75NTR mediates
NGF-induced death of cultured oligodendrocytes (Casaccia-Bonnefil et al 1996,
Gu et al 1999, Yoon et al 1998) and cultured hepatic stellate cells (Trim et al
2000), and BDNF signaling via p75NTR was shown to induce apoptosis of postnatal sympathetic neurons in culture (Bamji et al 1998). Moreover, an increased
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number of sympathetic neurons are found in BDNF-deficient mice, and there is

a delay in sympathetic cell death in p75NTR homozygous knockout mice (Bamji
et al 1998). BDNF-dependent trigeminal neurons are killed via binding of NT-4
to p75NTR, even though p75NTR is necessary to the cell survival induced by BDNF
(Agerman et al 1999). This indicates that p75NTR signaling is not only dependent
on cell context but also on neurotrophin binding specificity.
Ceramide Signaling One signal transduction pathway ascribed to p75NTR that
may be involved in apoptotic signaling involves generation of the lipid second
messenger ceramide via activation of sphingomyelinase. In fibroblasts expressing
p75NTR but not TrkA, NGF induced the production of ceramide. Furthermore, in
T9 glioma cells, NGF induced the activation of sphingomyelinase and the production of ceramide, and inhibited growth and fiber formation, a process that was
mimicked by incubation with membrane-permeant ceramide analogs (Dobrowsky
et al 1994). Other members of the p75NTR superfamily, such as TNF-RI and Fas,
also signal via ceramide production (Cifone et al 1994). This signaling function
appears to be mediated at least in part by a region within TNF-RI and Fas termed
the death domain, a C-terminal region in the cytoplasmic domain that is necessary
for apoptotic signaling downstream from these receptors (Tartaglia et al 1993,
Watanabe-Fukunaga et al 1992). Analysis of the p75NTR sequence shows that a
homologous death domain region exists within the intracellular region of this receptor (Liepinsh et al 1997). Recent experiments suggest that the death domain
serves to mediate protein:protein interactions. For example, this region mediates
Fas and TNF-RI intracellular domain aggregation (Boldin et al 1995a, Song et al
1994), and a homologous region has been found within ankyrin, a protein that
anchors transmembrane proteins to the cytoskeleton (Boldin et al 1995b).
Chopper Another death signaling domain was recently discovered within the
p75NTR juxtamembrane region. This domain, a 29-residue sequence named chopper, is necessary and sufficient to induce cell death in several cell types, including
neurons. It is interesting that a peptide corresponding to the chopper domain only
signaled cell death when associated with the plasma membrane via a lipid anchor.
Nonanchored chopper peptide did not mediate cell death and, in fact, acted in
a dominant-negative manner to p75NTR-mediated death signaling (Coulson et al
2000), suggesting that palmitoylation of p75NTR is a crucial factor in mediating
signaling from the receptor. This finding also suggests the possibility that proteolytic cleavage of the intracellular domain may play a role in controlling p75NTR
signaling.
Ligand-Independent p75NTR Signaling Another possible mechanism of p75NTRmediated cell death was suggested by the observation that overexpression of the
intracellular domain of p75NTR induced cell death in several neuronal populations
within the central and peripheral nervous systems (Majdan et al 1997). This finding, plus the observation that immortalized neural cells overexpressing p75NTR
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exhibit enhanced cell death following serum withdrawal (Rabizadeh et al 1993),

suggests that p75NTR may signal pro-apoptotically in the absence of ligand binding. In this model, binding of NGF to p75NTR induces a conformational change
that blocks the production of a death signal. Further support for this idea comes
from work showing that antisense-induced downregulation of p75NTR in neonatal
dorsal root ganglia sensory neurons enhanced survival (Barrett & Bartlett. 1994).
Moreover, identification of an alternatively spliced isoform of p75NTR lacking the
neurotrophin-binding domain supports the model of ligand-independent signaling
(Dechant & Barde 1997). The receptor produced by this alternative splice event
contains the transmembrane and intracellular domains, but lacks the ability to bind
neurotrophin and may therefore exhibit enhanced cell death signaling consistent
with the function of the death domains described above. Finally, p75NTR appears
to exhibit ligand-independent signaling through the RhoA pathway. In cells transfected with p75NTR, RhoA activation was generated in the absence of ligand and
was abolished by addition of ligand, suggesting that p75NTR can signal to reorganize the actin cytoskeleton in a manner that is negatively modulated by the presence
of neurotrophin (Yamashita et al 1999b).
NF
B Pathway Many proteins in the p75NTR superfamily interact with TNF
receptor-associated factors (TRAFs) that modulate signaling through the JNK and
NFB pathways. Six such factors have been identified in signaling evoked by TNFR, CD30, CD40, and the IL-1 receptor (Arch et al 1998, Rothe et al 1995), and
recently p75NTR was shown to associate with TRAF-2, TRAF-4, and TRAF-6 following treatment with NGF (Khursigara et al 1999, Ye et al 1999). Interestingly, the
association of TRAF-6 with p75NTR is mediated by the receptors juxtamembrane
domain (Khursigara et al 1999) within a sequence that is absolutely conserved
between human, rat, and chicken p75NTR (Large et al 1989), suggesting that the
interaction with TRAF-6 is critical to p75NTR function. TRAF-6 is recruited to the
IL-1 receptor via binding to IRAK, the IL-1 receptor-associated serine-threonine
kinase (Cao et al 1996a,b), and TRAF-6 also signals through NIK, the NFB inducing kinase (Malinin et al 1997), suggesting that one role of the p75NTR-(TRAF-6)
interaction may be to couple p75NTR to several different kinase cascades. The
use of adaptor proteins such as TRAF-6 potentially permits p75NTR, which lacks
any intrinsic kinase activity, to recruit and noncatalytically activate several cytoplasmic nonreceptor kinases, thereby linking NGF binding to p75NTR to NFB
activation.
In addition to apoptosis-related signaling, p75NTR binding of NGF also activates
the transcription factor NFB in neuroblastoma cells (Korner et al 1994), cultured
sensory and sympathetic neurons (Maggirwar et al 1998, Wood 1995), Schwann
cells (Carter et al 1996, Khursigara et al 1999), and oligodendrocytes (Ladiwala
et al 1998, Yoon et al 1998). The activation of NFB downstream from most
inducer proteins involves the degradation of the IB protein, an inhibitory factor
that binds heterodimers of the NFB p50 and p65 subunits and prevents them
from translocating into the nucleus (Ghosh et al 1998). IB degradation results
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in NFB nuclear translocation and in upregulated transcription of several genes,

including the IB gene. In oligodendrocytes, in which p75NTR appears to signal
via both NFB and the JNK pathway, expression of TrkA abrogates NGF-induced
cell death in a manner that correlates with cessation of JNK signaling, whereas
the NFB signal downstream from p75NTR is unaffected (Yoon et al 1998). This
suggests that p75NTR may evoke two separate pathways, one pro-apoptotic, the
other anti-apoptotic. The balance of these two pathways, as modulated by TrkA
signaling in some cells, may control the ultimate fate of the cell. However, the exact
role that NFB plays is unresolvedin some systems it exhibits anti-apoptotic
signaling (Maggirwar et al 1998, Mattson et al 1997), but in others it is associated
with pro-apoptotic signaling (Schneider et al 1999, Schwaninger et al 1999). The
TNF receptor, generally associated with death signaling, also activates NFB in a
pathway that appears to promote survival of lymphoid cells and fibroblasts (Liu et al
1996, Van Antwerp et al 1996, Wang et al 1996). Likewise, in hippocampal neurons
that do not express TrkA, NGF signaling through p75NTR protects these cells from
glucose deprivation-induced apoptosis (Cheng & Mattson 1991). Furthermore,
p75NTR appears to play a role in protecting Schwann cells following axotomy. In
the normal adult animal, Schwann cells do not express p75NTR. However, following
nerve injury, Schwann cells distal to the injury site dramatically upregulate p75NTR
expression (Heumann et al 1987b, Taniuchi et al 1986), and exhibit increased NFB
activation (Gentry et al 2000). This increase in NFB activation is correlated with
the absence of apoptosis in Schwann cells distal to the injury (Grinspan et al 1996).
It is interesting that during development Schwann cells require axonal contact for
trophic support, and loss of such contact results in cell death. Hence, injury induced
expression of p75NTR and consequent signaling through NFB may serve in the
adult to maintain Schwann cells in the absence of trophic support from the axon,
thereby providing time for the axon to regrow.
Interactions Between p75NTR and TrkA

Prior to defining p75NTR signaling pathways, a great deal of attention was focused
on a role for p75NTR in regulating NGF signaling through TrkA. A wealth of data
show that p75NTR does impact TrkA signal transduction. It does so by enhancing
binding of NGF to TrkA, by increasing the specificity of TrkA for NGF binding,
and through effects on TrkA signal transduction. Moreover, TrkA signaling also
impacts signaling through p75NTR. These efffects may be mediated, at least in part,
through the direct association of TrkA and p75NTR, as revealed in studies using
a variety of techniques, including photobleaching (Wolf et al 1995), copatching
(Ross et al 1996), cross-linking (Ross et al 1998), and coimmunoprecipitation
(Bibel et al 1999, Gargano et al 1997, Huber & Chao 1995). Recently, TrkA
and p75NTR were colocalized to caveolae-like domains of PC12 cells, and both
TrkA (Huang et al 1999) and p75NTR (Bilderback et al 1997) signal from these
membranes. These findings highlight an important additional level of complexity
for NGF signaling and point to the need for understanding the cell biology of
receptor trafficking and signaling.
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There are two classes of binding sites for NGF: Low-affinity receptors bind
NGF with nanomolar affinity, whereas high-affinity receptors bind NGF with an
affinity that is 100-fold greater (i.e. 1011 M) (Meakin & Shooter 1992, Sutter et al
1979). The two classes are distinguished by the much slower rate of dissociation
from high-affinity receptors (Landreth & Shooter 1980, Meakin & Shooter 1992,
Schechter & Bothwell 1981, Woodruff & Neet 1986). High-affinity receptors are
thought to play an important role in mediating NGF actions. Dissociation of NGF
from TrkA is slow (Meakin et al 1992), which suggests that TrkA contributes to the
formation of these receptors. TrkA is often referred to as the high-affinity receptor,
a designation that suggests TrkA alone binds NGF with high affinity. However,
although there is a small amount of high-affinity binding of NGF in cells expressing
only TrkA, most NGF binding to such cells is of low affinity (Mahadeo et al 1994).
In fact, most high-affinity binding appears to reflect the interaction of p75NTR with
TrkA. p75NTR has been shown to increase the rate of association of NGF with
TrkA, thereby increasing the number of high-affinity receptors (Mahadeo et al
1994). Moreover, p75NTR enhances activation of TrkA (Barker & Shooter 1994).
Of note, a recent study showed that some receptor complexes from which NGF
was slowly released contained p75NTR (Huang et al 1999).
p75NTR may also interact with TrkA to modify binding specificity. In fibroblasts
that express only TrkA, NT-3 and NT-4/5 are able to activate the receptor, whereas
in PC12 cells, which express both p75NTR and TrkA, only NGF is able to activate
TrkA (Berkemeier et al 1991, Ip et al 1993). Likewise, mutant PC12 cells that
express only very low levels of p75NTR exhibit NT-3-induced TrkA activation
(Benedetti et al 1993). Finally, postnatal sympathetic neurons normally exhibit very
limited survival in culture in response to NT-3, but these same neurons isolated from
p75NTR transgenic knockout mice show a much more robust NT-3-induced survival
response (Lee et al 1994c). These data suggest that p75NTR may function to tune
individual neurons to specific neurotrophin responsiveness, thereby controlling the
ability of such neurons to compete for target-derived neurotrophic support. It is
interesting to note that sympathetic neurons normally undergo a switch in trophic
dependence, from an early dependence upon NT-3 to a later dependence on NGF,
and that this switch is temporally correlated to the onset of p75NTR expression
(Birren et al 1993). Furthermore, as NGF signaling via TrkA appears to control
p75NTR expression in these cells (Miller et al 1991, 1994; Verdi & Anderson
1994; Verge et al 1992; Wyatt et al 1990), it is possible that first contact between the innervating sympathetic fibers and NGF available from the target field
elicits the trophic dependency switch. Also, the expression of p75NTR by cells that
have received an NGF signal from the target may increase the sensitivity of those
neurons to low levels of target-derived NGF, leading to a situation in which those
neurons that express p75NTR are better able to compete for synaptic space within
the target. Hence, the ability of p75NTR to sharpen TrkA binding specificity may
play a significant role in the maturation of target innervation, and may control the
competition that defines the adult pattern of innervation. Whether p75NTR plays
such a role in synaptic competition within the central nervous system remains to
be determined.
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Perhaps the most interesting facet of the interaction of TrkA and p75NTR is
evidence for reciprocal effects on signaling. Barker and colleagues provided evidence that signaling through p75NTR inhibits signaling though TrkA. Addition
of BDNF to PC12 cells markedly reduced the TrkA activation and downstream
signaling events that were elicited by treatment with an NGF mutant that only
binds to TrkA (MacPhee & Barker 1997). BDNF is known to activate sphingomyelinase and increase ceramide levels (Dobrowsky et al 1995). Ceramide
addition produced changes similar to those seen with BDNF. It is interesting
that both BDNF and ceramide treatment were shown to increase phosphoserine
content on the intracellular domain of TrkA (MacPhee & Barker 1997), which
suggests that BDNF acts through p75NTR and ceramide production to influence
TrkA signaling. Completing the analysis of signaling interactions, there are examples in which TrkA has a negative or restraining effect on p75NTR signaling.
Although NGF effectively induced sphingomyelin hydrolysis in cells expressing
p75NTR in the absence of TrkA, NGF did not do so in PC12 cells. This effect
is apparently mediated by TrkA signaling because inhibition of TrkA signaling
by the inhibitor K252a restored the ability of NGF to hydrolyze sphingomyelin
(Dobrowsky et al 1995). In another example, when oligodendrocytes were transfected with TrkA, treatment with NGF induced activation of the MAPK pathway,
suppressed JNK activity, and prevented cell death without influencing the activation
of NFB (Yoon et al 1998). These studies document the existence of robust, reciprocal interactions between TrkA and p75NTR. An important goal is the elucidation
of the molecular basis for these interactions and the definition of their physiological
significance.
Signaling Endosomes
Internalization of the NGF-TrkA complex plays an important role in intracellular
signaling, particularly in neurons, where retrograde transport of the signal from
distant axon terminals is required to trigger signaling in the cell body. Considerable
evidence suggests that this internalization involves endocytosis and the formation
of signaling endosomes, organelles in which NGF continues to be bound to its
activated receptors (Grimes et al 1996, 1997; Riccio et al 1997; Tsui-Pierchala &
Ginty 1999; Ure & Campenot 1997; Watson et al 1999). TrkA and p75NTR activation appears to occur predominantly in caveolae-like membranes that contain
many of the intermediates of their signaling pathways (Bilderback et al 1999,
Huang et al 1999). It is possible that signaling endosomes are derived from these
membranes, but it is noteworthy that at least some TrkA appears to be internalized
via clathrin-coated membranes (CL Howe, JS Valletta, WC Mobley, submitted
for publication). In fact, in recent studies we have shown that NGF increased the
association of clathrin with membranes and induced the formation of complexes
containing activated TrkA, clathrin heavy chain, and the plasma membrane specific adaptor complex, AP2. Moreover, we discovered that clathrin-coated vesicles
isolated from NGF-treated cells contained NGF bound to activated TrkA, linking
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formation of the TrkAclathrin complex to endocytosis via clathrin-coated membranes. It is exciting to note that Shc was recruited to these membranes, as was
Ras and activated Erk1/2. Importantly, we found that NGF-induced clathrin-coated
vesicles were able to signal in an in vitro kinase assay to propagate the NGF signal from Erk to Elk. Our findings indicate that NGF signals from endosomes and
that clathrin-coated vesicles are one source of signaling endosomes produced in
response to NGF treatment (CL Howe, JS Valletta, WC Mobley, submitted for publication). In other recent work, we have also isolated additional membranes that
contain the NGF signal, suggesting the existence of a variety of signaling endosome species (CB Wu, CF Lai, WC Mobley, submitted for publication). Whether
p75NTR signals from endosomes is an interesting possibility that requires further
study, though preliminary evidence suggests that p75NTR does utilize the clathrin
pathway for internalization, hinting at the existence of clathrin-coated vesicles
that contain p75NTR and p75NTR-associated signaling elements (CL Howe, AP
Kruttgen, E Shooter, WC Mobley, unpublished observations). These findings are
consistent with the concept that NGF signaling initiates the endocytosis of specialized membrane regions to form signaling endosomes that are enriched both in NGF
receptors and their downstream signaling second-messenger target molecules.
Signaling endosomes may exist as signaling complexes in the cytoplasm that
can be transported from the site of their formation along neurites to the cell
body.
Positive Feedback
There are several means by which positive feedback could be exerted in NGF
signaling loops. First, as described above, NGF upregulates the expression of its
own receptors. Second, NGF upregulates expression of such effector molecules
as acetylcholine (Mobley et al 1985) or substance P and related tachykinins
(Lindsay & Harmar 1989), which on their release would be expected to upregulate
the expression of NGF by target tissues (Berzaghi et al 1993, French et al 1999,
Woolf et al 1994). These changes may lead to reinforcement and strengthening of
NGF signaling in a positive feedback manner (Sofroniew & Mobley 1993). The
functional consequences of these effects are poorly understood. In nociceptive neurons, NGF upregulates the expression of neuropeptides such as substance P and calcitonin gene-related peptide, and positive feedback in this system may facilitate the
induction of sensitization and hyperalgesia in response to tissue injury (Malcangio
et al 1997; Mendell 1996; Verge et al 1995, 1996). In the forebrain, positive feedback may represent a means of reinforcing heavily used cholinergic connections,
with significant ramifications for learning- and memory-related plasticity (Howe &
Mobley 2001).
Interactions Between NGF and Other Molecular Signaling

Glutamate Both NGF and glutamate signaling have well documented effects
on the regulation of neuronal survival and neurite outgrowth during development.
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Reports also exist of synergistic interactions between glutamate and NGF (CohenCory et al 1991) or other neurotrophins (Morrison & Mason 1998) in sculpting
neuronal survival or morphology during development. Interactions between glutamate and neurotrophin signaling that modulate neuronal excitablility persist in
mature neurons (McAllister 1999). The intracellular signaling mechanisms involved in these effects are not yet known, and evidence for direct convergence
of intracellular signaling mechanisms has not yet been reported, but it appears
possible along several pathways, including modulation of cytoplasmic Ca2+ levels
(Mattson 1996).
Estrogen Estrogen enhances neuronal growth and differentiation and regulates
cytoskeletal and growth-associated gene expression. There is now evidence for
both colocalization of estrogen and NGF receptors in the same cells (ToranAllerand et al 1992), and for direct convergence of NGF and estrogen signaling
through the MAPK pathway (Singer et al 1999, Singh et al 1999). Such mechanisms
may contribute to the many modulatory effects of estrogen on neural function. An
important unresolved issue is how estrogen signals to induce MAPK activation.
Intracellular Signals Much attention has focused on NGF signaling effects on
intracellular Ca2+, and there is reason to believe that Ca2+ plays an important role
in many aspects of the biology of NGF and the other neurotrophins. In recent studies using PC12 cells, and fibroblasts transfected with TrkA or p75NTR, NGF was
shown to signal through TrkA and p75NTR to cause acute and transient increases
in intracellular Ca2+ as a result of increased uptake through L-type Ca2+ channels
(Jia et al 1999, Jiang et al 1999). TrkA activation also increased intracellular Ca2+
mobilization (Jiang et al 1999). A number of functions can be envisioned for the
increased intracellular Ca2+ that follows NGF treatment. The Ca2+ set point hypothesis posits that the level of cytoplasmic Ca2+ determines the degree of NGF
signaling required to suppress cell death mechanisms during development (Johnson & Deckwerth 1993). Effects of NGF signaling on cytoplasmic Ca2+ levels also
represent a means for NGF to influence the plasticity and vulnerability of mature
neurons (Mattson et al 1995). It is tempting to suggest that through acute changes
in intracellular Ca2+, NGF could influence the behavior of synapses through
increased release of neurotransmitters or of other neurotrophins (Berninger &
Poo 1996, Kruttgen et al 1998).
EFFECTS AND FUNCTIONS OF NGF

Given the many cell types expressing NGF and NGF receptors, and the diverse
intracellular signaling cascades triggered by NGF, it is not surprising that NGF
signaling is implicated in many different functions during development and in
adults. NGF mediates several types of intercellular communication and has been
shown to act as (a) a retrogradely transported, target-derived factor that influences
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afferent neurons, (b) a locally released paracrine factor that affects both neurons
and nonneuronal cells, (c) an autocrine factor acting on the same cells that produce
and release it, and (d) an endocrine factor that acts after transport through the blood
stream (Levi-Montalcini et al 1995, 1996).

NGF Roles in Development

NGF has a number of roles in the development of neuronal and nonneuronal cells.
During development NGF promotes the survival and maturation of several populations of neurons that express TrkA and p75NTR: in the PNS, sympathetic and
sensory neurons (Conover & Yancopoulos 1997, Johnson et al 1986, Lehmann
et al 1999, Snider 1994) and in the CNS, basal forebrain, and striatal cholinergic
neurons (Kew et al 1996, Li et al 1995, Svendsen et al 1994). For each of these populations, NGF participates in classical target-derived neurotrophic relationships.
The importance of these relationships is evident from the results of experiments
in which the genes for NGF or the NGF receptors were disrupted. Knocking out
the NGF gene resulted in the loss of most small nociceptive dorsal root ganglion
(DRG) neurons and sympathetic neurons in the PNS (Crowley et al 1994). In the
CNS of animals heterozygous for disruption of the NGF gene, there was a clear
reduction in the number of basal forebrain cholinergic neurons, atrophy of these
cells, and reduction in the cholinergic innervation of the hippocampus (Chen et al
1997). Further study is needed to explore the effect of NGF gene disruption on
striatal cholinergic neurons. However, both basal forebrain and striatal cholinergic
neurons are reduced in number and size in animals in which the gene for TrkA was
disrupted (Fagan et al 1997). Also, there was marked depletion of both small DRG
neurons and sympathetic neurons in TrkA knockout animals (Smeyne et al 1994).
Changes are also seen with p75NTR gene disruption in both the PNS and CNS.
In the PNS, there are defects in sensory innervation of skin and in sympathetic
innervation of the pineal gland and sweat glands (Lee 1992, 1994b,c). Remarkably,
disrupting the gene for p75NTR had little if any effect on the number of sympathetic
neurons in animals in which both copies of the NGF gene were present (Brennan
et al 1999). However, disrupting p75NTR increased the number of sympathetic neurons in animals in which the NGF gene was also disrupted (Brennan et al 1999).
The mechanism for this surprising and interesting result is not yet established.
However, one possible interpretation is that NGF signaling through p75NTR restrains the normal survival and development of sympathetic neurons. Another is
that p75NTR gene disruption allows NT-3 to signal through TrkA to enhance neuron survival, a suggestion for which there is experimental evidence (Brennan et al
1999). Further studies will be needed to clarify the interaction.
Paralleling the results for sympathetic neurons, p75NTR gene disruption appears
to increase the number and size of basal forebrain cholinergic neurons (Greferath
et al 2000, Yeo et al 1997, but see Peterson et al 1999). While it is interesting
to speculate that p75NTR signaling inhibits the normal development and function
of these neurons, the mechanistic basis for this is yet to be determined. Though
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additional studies are required to detail NGF effects in the developing nervous
system, gene disruption studies have documented an important role for NGF in
the survival and differentiation of both PNS and CNS neurons.
Interesting additional themes have emerged that have considerably modified
the original neurotrophic hypothesis. First, CNS and PNS neurons are not continuously dependent on the constitutive supply of a single target-derived factor
throughout life. Rather, a variety of different molecules from different sources
influence developmental survival and maturation. For example, sensory neurons
are transiently dependent for survival on different neurotrophins at different time
points as they progress through phases of development (Davies 1994). Second,
transiently required growth factors may derive from sources other than the final
target region, such as local interactions around the cell bodies (Enokido et al 1999),
or intermediate targets that axons encounter and then grow past en route to final
destinations (Wang & Tessier-Lavigne 1999). Third, NGF signaling can also mediate axon sprouting, as well as growth cone turning and local guidance (Campenot
1977, Gallo et al 1997, Patel et al 2000, Rice et al 1998, Tuttle & OLeary 1998).
For example, a recent study shows that NGF is critical for the elongation of the peripheral but not the central processes of sensory neurons (Patel et al 2000). Fourth,
NGF can also induce the death of certain developing neurons by signaling through
p75NTR in the absence of TrkA, as in the retina (Frade & Barde 1998, Frade et al
1996). Regarding glia, NGF may regulate the development of oligodendrocytes,
but here too, rather than promoting survival, NGF signaling via p75NTR can under
certain circumstances induce the death of these cells (Casaccia-Bonnefil et al 1996,
Chao et al 1998, Gu et al 1999). Taken together, these findings point to the complex
neurotrophic environment that guides the development of the nervous system. A
role for TrkA signaling in NGF actions during development is well established and
appears to be the dominant theme in signaling events that are required for survival
and differentiation. Nevertheless, it is apparent that p75NTR has important roles to
play in modulation of TrkA signaling and may also independently regulate cell
survival. The stage is now set for exploring the details of NGF signaling in the
developing nervous system.
NGF Roles in Adults

Both NGF and NGF receptors continue to be expressed and dynamically regulated
by many different cells types throughout adult life and aging. Information about
different NGF functions in adults is emerging for both NGF-responsive neurons
and nonneuronal cell types. Once mature, most neurons lose absolute dependence
on target-derived growth factors for acute survival. In adults, the focus of NGF
signaling shifts away from the regulation of neuronal survival to the regulation
of neuronal phenotype and function. In cases well studied thus far, CNS and
PNS neurons that are developmentally dependent upon NGF for survival become
independent of a constitutive supply of target-derived NGF for acute survival once
they have established their connections and reached maturity. In adults, sensory
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and CNS cholinergic neurons do not die for many months after NGF withdrawal
(Johnson & Deckwerth 1993; Sofroniew et al 1990, 1993; Svendsen et al 1994).
Adult sympathetic neurons also do not die acutely after immunologically induced
NGF withdrawal; instead, they undergo a gradual cell death of about 25% after
one month, which increases to about 40% after 3 months (Ruit et al 1990). The
resistance of these neurons to NGF withdrawal may be caused by loss of the cfos induction that normally follows such withdrawal in young neurons and by
consequent interruption of a cascade that involves both c-fos and Bax (Easton et al
1997). Although these mature NGF-responsive neurons become independent of
NGF for acute survival, they all undergo atrophic changes if subjected to NGF
withdrawal. These changes take the form of cell shrinkage (which is often severe)
and reduced transmitter-related gene expression.
It is likely that TrkA signaling mechanisms are implicated in these changes,
since NGF has been shown to increase cell size in neurons that do not express
p75NTR (Holtzman et al 1995). Because mature NGF receptor expressing neurons
do not require a constitutive supply of NGF for acute survival, the possibility exists that acute fluctuations in NGF signaling dynamically regulate various types
of activities in mature NGF-responsive cells. As discussed in this section, these
functions include modulation of the plasticity of NGF-responsive neurons. A particularly well-documented and striking example of this is the regulation by NGF
of mature nociceptive neurons (Woolf et al 1996).
The widespread production of NGF by glial cells and other nonneuronal cells
is leading to new ideas about other types of NGF functions, prominent among
which appear to be roles in inflammation and the response to injury in the CNS,
PNS, and peripheral tissue. NGF appears likely to have other functions that are
currently not well understood. For example, NGF infused into the lateral cerebral
ventricles induces hypophagia and weight loss in rats (Winkler et al 2000), and
NGF treatment has been reported to affect appetite in patients in clinical trials
(Petty et al 1994).
Plasticity of NGF-Responsive Neurons The adult nervous system exhibits a
remarkable ability to alter both its structure and function in response to stimuli,
a capacity commonly referred to as plasticity. Neurotrophins are implicated as
molecular mediators of specific forms of both structural and functional plasticity.
NGF has thus far been associated in particular with effects on structural plasticity and has far fewer reported direct effects on neuronal activity in comparison
with other neurotrophins, such as BDNF (McAllister 1999). Nevertheless, NGF
has reported effects on stimulus-dependent activity in adult somatosensory cortex
(Cellerino & Maffei 1996, Gu et al 1994, Prakash et al 1996) that appear to be mediated by TrkA and facilitated by p75NTR (Pizzorusso et al 1999). The mechanistic
basis for these effects is unclear but may involve NGF-dependent modulation of
cholinergic function and subsequent modification of cortical plasticity (Howe &
Mobley 2001). In the PNS, NGF regulates the cell body size, terminal sprouting, dendritic arborization, and gene expression of sympathetic neurons and small
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nociceptive sensory neurons (Johnson et al 1986, Ruit et al 1990). In the CNS,

NGF regulates the cell body size, dendritic arborization, terminal sprouting, and
gene expression of basal forebrain and striatal cholinergic neurons (Cuello 1996,
Debeir et al 1999, Howe & Mobley 2001). As discussed above, NGF increases the
expression of its own receptors, as well as of transmitters or transmitter-producing
enzymes, and may do so to modulate cell function in a context-specific manner.
It is interesting that in both the CNS and PNS, target-derived as well as locally
applied NGF will exert these effects, and there are both target-derived and local sources of NGF-producing cells available to the neurons. The significance of,
and interactions between, local and target-derived signaling for NGF-responsive
neurons are not yet understood.
Nociception Small nociceptive sensory neurons express both types of NGF receptor throughout life, and NGF has a variety of effects on these cells, including
upregulation of TrkA and p75NTR, CGRP (calcitonin gene related peptide), and
tachykinin expression, as well as modulation of cell size, activity, and neuropeptide release (Malcangio et al 1997; Mendell 1996; Verge et al 1995, 1996). NGF
signaling in these cells leads to hypersensitivity to nociceptive stimuli in the form
of allodynia and hyperalgesia in both animals and patients given NGF in clinical
trials for peripheral neuropathies (Petty et al 1994, Shu & Mendell 1999). NGF
is expressed and released in many tissues in response to injury, and blockade of
NGF signaling using function blocking antibodies in experimental animals with
skin injury and inflammation prevents the development of hyperalgesia (McMahon
et al 1995). NGF elicits both mechanical and thermal hyperalgesia. With respect
to the latter, NGF acts as a peripheral sensitizing agent to alter the response of
nociceptors to noxious stimuli. It may accomplish this effect in part by inducing
mast cell degranulation and the consequent release of serotonin, histamine, and
NGF itself (Shu & Mendell 1999). In terms of mechanical hyperalgesia, NGF
may act centrally by upregulating CGRP, substance P, and BDNF (Shu & Mendell
1999). Recent findings suggest that PKC may mediate the actions of NGF on peripheral nociception (Khasar et al 1999). Thus, NGF plays an important role in
the nociceptive response that follows tissue injury by inducing both peripheral and
central sensitization through signaling that involves several cell types, including
leukocytes and nociceptive sensory and sympathetic neurons (Mendell et al 1999,
Shu & Mendell 1999, Woolf et al 1996). NGF may also be an important mediator
in pain due to visceral inflammation (Dmitrieva et al 1997) and in neuropathic pain
syndromes induced by peripheral nerve irritation.
Immune and Inflammatory System NGF has numerous effects on immune and
inflammatory cells that are generally directed at inducing their state of
activation and effector functions (Levi-Montalcini et al 1996, Otten et al 1994,
Simone et al 1999). NGF increases mast cell number, induces mast cell degranulation, and increases mast cell expression of cyclooxygenase and interleukin-6
(Marshall et al 1999, Simone et al 1999). NGF activates monocytes, macrophages,
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and CNS microglia by increasing their phagocytic activity and by inducing their
expression of interleukin-1, Fc receptor, and lysosomal proteases of the cathepsin
family (Liuzzo et al 1999; Susaki et al 1996, 1998). NGF is chemotactic for neutrophils (Gee et al 1983). NGF influences T and B lymphocyte proliferation, is an
autocrine survival factor for B lymphocytes, and stimulates immunoglobulin production (Levi-Montalcini et al 1996, Otten et al 1994, Torcia et al 1996). Through
its interactions with immune and inflammatory cells, as well as with glia and neurons, NGF has been suggested to play a role in various diseases with postulated
autoimmune and inflammatory components, including arthritis and demyelinating
diseases (Aloe 1998, Bonini et al 1999, Levi-Montalcini et al 1996).
NGF AND NEUROPROTECTION

Substantial evidence suggests that among other functions, NGF acts to protect neurons from endogenous toxic events generated during the response to tissue injury
and that NGF signaling facilitates regrowth and repair. The signaling mechanisms
engaged in neuroprotection have not been defined. However, it appears that the
protective effects of NGF extend both to neurons known to express NGF receptors
and to those that are not known to express such receptors.
NGF Protection of Neurons Known to Express NGF Receptors

Protection from Axotomy Throughout the PNS and CNS, adult neurons vary
considerably in their vulnerability to axotomy. For unknown reasons, some axotomized neurons survive with few obvious changes, others survive but atrophy to
moderate or severe degrees, and others die either rapidly or over a prolonged time
course (Sofroniew 1999). Among NGF-responsive neurons, sensory neurons and
cholinergic neurons in the basal nucleus survive axotomy but exhibit moderateto-severe atrophy (Sofroniew et al 1983, Verge et al 1996). In contrast, about 50%
(but not all) of axotomized sympathetic neurons and septal cholinergic neurons
rapidly die (OBrien et al 1990, Ruit et al 1990, Tuszynski et al 1990). Neither the
mechanism of axotomy-induced cell death, nor the reasons that some neurons die
while others survive but atrophy, are understood. In the adult septum, axotomyinduced cell death is not due to loss of NGF signaling because target lesion and
NGF-depletion studies show that these neurons are not acutely dependent on NGF
for survival (Kordower et al 1993; Sofroniew et al 1990, 1993). Nevertheless, the
death of these neurons can be largely prevented in both rodents and primates by
NGF infusions at the time of the axotomy (Hefti 1986, Tuszynski & Gage 1995b,
Williams et al 1986). In the septum, this effect appears to be mediated via TrkA
signaling (Lucidi-Phillipi et al 1996), and NGF need only be given transiently for
a few weeks after the axotomy and can then be discontinued without subsequent
loss of neurons (Tuszynski & Gage 1995a). In addition, NGF is able to prevent
axotomy-induced atrophy in cells that are not killed by axotomy, as well as to
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reverse atrophy that has already occurred (Cuello 1994). The intracellular pathways through which NGF signaling protects TrkA and p75NTR expressing neurons
from axotomy-induced death are not defined.
Protection from Glutamate Excitotoxicity Aloe (1987) first reported a protective effect of NGF against glutamate receptormediated excitotoxicity, such that
NGF infusions reduced the overall size of excitotoxic lesions in the striatum and
prevented the death of cholinergic, NGF receptorexpressing, striatal neurons.
These observations have been confirmed by others using local infusions of NGF
or grafts of cells genetically modified to secrete NGF (Davies & Beardsall 1992,
Frim et al 1993, Martinex-Serrano & Bjorklund 1996, Schumacher et al 1991).
NGF has also been reported to protect PC12 cells from anoxia and glucose deprivation, or from nitric oxide cytotoxicity (Boniece & Wagner 1993, Wada et al 1996).
To examine the potential role of endogenous NGF signaling in the protection of
NGF-responsive neurons from excitotoxicity, we recently studied septal cholinergic neurons that express NGF receptors and project to hippocampus and are thus,
in contrast to striatal cholinergic neurons, well separated from their target cells that
produce NGF. Both local and target-derived (i.e. retrogradely transported) NGF
signaling significantly attenuated glutamate receptormediated excitotoxic death
of these neurons in young adult rats. In addition, aged rats that have a reduced
capacity to retrogradely transport NGF, and young adult rats given target lesions
that deplete access to retrogradely derived NGF, both exhibited (a) significantly
increased vulnerability of cholinergic neurons to glutamate receptormediated
toxicity, (b) significantly reduced protective effects of local NGF, and (c) significantly reduced levels of TrkA. Chronic intracerebroventricular NGF significantly
restored TrkA and the protective effect of local NGF (Horner et al 1999; HHD
Lam, CH Horner, J Berke, JD Cooper, RE Brown, SB Dunnett, MV Sofroniew,
submitted for publication). These findings suggest that in adult forebrain, signaling through TrkA serves ongoing neuroprotective functions. They also suggest that
loss of endogenous NGF signaling leads to increased vulnerability of these cells to
excitotoxicity. However, the intracellular pathways through which NGF signaling
protects TrkA and p75NTR expressing neurons from glutamate receptormediated
death are not yet defined.
NGF Protection of CNS Neurons that do

not Appear to Express NGF Receptors
Although readily detectable expression of TrkA and p75NTR is confined to relatively few populations of neurons in both the PNS and CNS, NGF is reported to
protect a broad spectrum of neurons from ischemia, glutamate receptormediated
excitotoxicity, and metabolic insults such as glucose deprivation and oxidative
stress. Protective effects of NGF on neurons not known to express NGF receptors have been described and confirmed by numerous research groups using many
different in vivo and in vitro models.
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Protection from Glutamate Excitotoxicity and Ischemia In Vivo The initial

report by Aloe (1987) of NGF protection from glutamate receptormediated excitotoxicity in striatum described a reduction in lesion size greater than that which
would be expected if only TrkA- and p75NTR-expressing neurons had been protected. A generalized and widespread neuroprotective effect of NGF has been
confirmed in several in vivo experimental models. In response to excitotoxic glutamate analogues infused into the striatum, widespread and generalized neuronal
protection is achieved both by simultaneous direct infusions of NGF (Holtzman
et al 1996) and by previously placed grafts of genetically modified cells (using various different cell types) that express and release NGF (Frim et al 1993,
Martinex-Serrano & Bjorklund 1996, Schumacher et al 1991). In addition, NGF
delivered by infusion, grafts, or transgenic expression or induced in astrocytes by
2-adrenoreceptor activation protects diverse populations of retinal, hippocampal, cortical, and other forebrain neurons that do not express detectable levels of
TrkA and p75NTR from ischemia or excitotoxic glutamate analogues (Culmsee et al
1999, Guegan et al 1997, Shigeno et al 1991, Siliprandi et al 1993). It is interesting
that neutralizing antibodies to NGF block the protective effects of interleukin-1
against glutamate excitotoxicity, further indicating that endogenous NGF can exert
widespread protection (Carlson et al 1999, Strijbos & Rothwell 1995).
Protection from Toxins and Metabolic Insults In Vitro NGF neuroprotective
effects have been described and characterized extensively in vitro for many types
of neurons not known to express TrkA and p75NTR. NGF protects cortical, hippocampal, striatal, retinal, and other types of neurons grown in dispersed cell
tissue cultures from glutamate excitotoxicity, hypoglycemia, and oxidative stress,
as first reported by Mattson and colleagues (Cheng & Mattson 1991, Mattson et al
1995) and confirmed, and extended to include ethanol toxicity, in many laboratories (Cunha et al 1998, Heaton et al 1993, Luo et al 1997, Mattson & Marck 1996,
Singer et al 1999).
Potential Mechanisms of NGF-Mediated Neuroprotection of Non-NGF
Receptor-Expressing Neurons The signaling mechanisms underlying NGFmediated protection of neurons that do not express NGF receptors are not understood. In some cases, protection has been shown to involve stabilization of
intracellular Ca2+ levels and prevention of the surge in cytoplasmic Ca2+ associated with cell death, as triggered by excess glutamate signaling or oxidative stress
(Mattson 1996). In a recent study, protection of cortical neurons from glutamate
excitotoxicity in vitro by both NGF and estrogen were found to require activation
of the MAPK pathway (Singer et al 1999). The means by which NGF signaling
leads to widespread neuroprotective effects is not known, and there are several
different options to consider. The first is simply that TrkA and p75NTR expression is more widespread among neurons than is currently appreciated, and very
low levels of TrkA or p75NTR might be able to mediate the protective signaling.
The second option is that a novel NGF receptor exists that is widely expressed.
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It is difficult simply to dismiss this possibility. Although radiolabeled NGF binding to brain sections defines the known NGF-responsive populations, Altar et al
(1991) also found significant binding in the hippocampus, in the subiculum, and
in the cingulate, frontal, parietal, and occipital cortex. It is likely that much of this
binding is attributable to NGF receptor expression on the axons of known NGF
responsive neurons. However, the formal possibility also exists that this binding
represents the expression of a novel receptor on cells in these regions. A third
option is that widespread neuroprotective effects of NGF on neurons that do not
appear to express TrkA and p75NTR are mediated via NGF signaling through such
NGF-responsive nonneuronal cells as glia and inflammatory cells. Several lines
of evidence support this possibility. As described above, nonneuronal cells (a)
express both NGF and NGF receptors, and expression is generally upregulated
by injury and other CNS insults, (b) respond to NGF signaling, and (c) generate
molecules that are potentially toxic to neurons, such as nitric oxide and reactive
oxygen species, as part of their response to injury and inflammation. Potentially
neuroprotective effects of NGF include the rapid inhibition of reactive oxygen
species generation in vitro (Dugan et al 1997) and the rapid inhibition of basal and
glutamate receptorinduced nitric oxide synthase in vivo (Lam et al 1998).
NGF AND NEURAL REPAIR

The molecular signals that control cellular interactions during the response to
injury and attempts at repair in the PNS and CNS are beginning to be understood.
Available evidence suggests a complex interplay of molecules, including numerous
growth factors and cytokines. Changes in the expression of NGF and NGF receptors
in both PNS and CNS are compatible with roles in repair, and their involvement
warrants further investigation.
NGF and PNS Repair

Glia and Inflammatory Cells After a peripheral nerve injury that causes axotomy, both meylinating and nonmyelinating Schwann cells distal to the injury dedifferentiate and reenter the cell cycle. Proliferating and reactive Schwann cells produce growth factors, cytokines, and growth-associated proteins, which are likely to
play key roles in axon regeneration and nerve repair (Frostick et al 1998, Mirsky &
Jessen 1999, Verge et al 1996). Changes in gene expression by reactive Schwann
cells include a marked upregulation of both NGF and p75NTR (Frostick et al 1998,
Lindholm et al 1987, Mirsky & Jessen 1999). Peripheral nerve injury also leads
to substantial infiltration of inflammatory cells, and among these, macrophages,
mast cells, and subsets of T cells have the capacity to express NGF. The precise
roles and functions of NGF signaling for different cell types during the response to
peripheral nerve injury are not certain. An overall effect of exogenously administered NGF is to increase both the number and myelination of regenerating axons in
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experimental entubation repair in which transected peripheral nerve stumps regrow

through bridging tubes containing artificial matrices (Derby et al 1993, Rich et al
1989). This may be due to effects of NGF signaling both on regenerating nerve
fibers, as discussed below, and on Schwann and inflammatory cells. Exogenous
NGF promotes Schwann cell migration (Anton et al 1994), and Schwann cell migration is thought to precede and promote axon elongation into entubation repair
sites (Madison & Archibald 1994). Denervation is the trigger for Schwann cell
production of NGF and NGF receptors, and the proximity of regenerating axons
suppresses this expression, probably through diffusible molecules (Taniuchi et al
1988). Downregulation of p75NTR on Schwann cells induced by contact with axons
is likely to lead to Schwann cell accumulation around regenerating axons and may
promote eventual remyelination (Madison & Archibald 1994).
Neurons NGF receptor expression in peripheral nerve cells changes after axotomy; TrkA and p75NTR expression by sensory neurons decreases (Verge et al
1996), whereas motor neurons begin to reexpress detectable levels of p75NTR
(Ernfors et al 1988, Wood et al 1990). Neither the reasons for, nor the consequences of, the decline in TrkA expression by axotomized sensory neurons are
understood. Nevertheless, sensory neurons regenerate robustly and, after regeneration, reexpress TrkA at preinjury levels. As described above, motor neurons
express high levels of p75NTR during the period of axon outgrowth during development and downregulate expression to undetectable levels after contact with target
structures. After injury in adult PNS, motor neurons that are allowed to regenerate
recapitulate this developmental event and reexpress p75NTR during the period of
axon regeneration. Reexpression does not occur in neurons that are not allowed to
regenerate and requires retrograde transport from axons growing through injured
peripheral nerve tissue (Bussmann & Sofroniew 1999, Wood et al 1990). It is not
yet clear whether p75NTR reexpression plays an essential role in the regeneration
of either sensory or motor neurons; however, recent findings show that p75NTR signaling through Rho and ceramide pathways may be involved in promoting axon
elongation (Brann et al 1999, Lehmann et al 1999, Yamashita et al 1999b).
NGF and CNS Repair

In the CNS, as in the PNS, injury or insults such as trauma, ischemia, or degenerative disease trigger rapid and substantial upregulation in the expression of NGF
and NGF receptors by cell types involved in the repair process, including (a) local
astrocytes and microglia, (b) invading inflammatory cells, including macrophages,
mast cells, and subsets of T cells, and (c) certain neurons. The purpose underlying such changes in expression levels is not yet known. Several lines of evidence
suggest that NGF signaling may in some of these instances facilitate the repair or
reorganization of neural connections.
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Axon Sprouting and Growth Forebrain cholinergic neurons that express TrkA
and p75NTR exhibit neurite outgrowth in response to NGF in adults, particularly
after injury (Heisenberg et al 1994, Kawaja & Gage 1991, Kordower et al 1994),
suggesting that NGF may stimulate regrowth and reorganziation of connectivity
of receptor bearing neurons after injury. Several other populations of CNS neurons
transiently express p75NTR during development and, in a manner similar to primary
motor neurons, downregulate this expression after maturity. These populations
include cerebellar Purkinje, hippocampal pyramidal neurons, and retinal neurons.
Whether these neurons reexpress p75NTR after injury, as do regenerating motor
neurons, and whether NGF signaling might increase their axon regeneration, as in
the PNS, is a point for further study. In support of this possibility, NGF induces
neurite outgrowth in developing hippocampal pyramidal neurons in vitro, via a
p75NTR-ceramidemediated signaling pathway (Brann et al 1999), and in retinal
neurons, p75NTR signaling activates Rho pathways, which have been associated
with axon growth (Lehmann et al 1999, Yamashita et al 1999b).
Other intriguing recent observations suggest that stimulation with NGF and
other growth factors may regulate the intrinsic capacity of neurons to regenerate
transected axons through the hostile extracellular environment of the injured adult
CNS. In adult spinal cord, NGF and other growth factor infusions stimulate the
regrowth of fibers of receptor-expressing sensory neurons across the PNS-CNS
border in a manner that does not occur in the absence of growth factor, which
suggests that the growth factors (including NGF) enabled these axons to overcome environmental cues that inhibit axon elongation in the CNS (Ramer et al
2000). The signaling mechanism for this effect is not established, but evidence
from other studies suggests it may involve cAMP. It has been known for some
time that if the peripheral nerves containing peripheral branches of DRG sensory
neurons receive two lesions within a short period of time, axon regeneration occurs more rapidly after the second injury. Moreover, a conditioning lesion made
to the peripheral branches of DRG neurons a number of days prior to a lesion
of the central branches results in increased regeneration of these central branches
into PNS-grafts (Richardson & Issa 1984). Neumann & Woolf (1999) recently
extended these observations by showing that a peripheral conditioning lesion also
enables considerable regeneration of the central branches of DRG neurons in the
absence of any other intervention after a second, delayed injury in the adult CNS.
The findings of Cai et al (1999) suggest a possible mechanism underlying these
observations by showing that NGF and other growth factors can mimic the effects
of peripheral conditioning lesions by increasing the capacity of DRG neurons to
grow on otherwise inhibitory CNS myelin substrates in vitro. The intracellular
signaling pathway for this effect involves elevation of neuronal cAMP levels and
requires PKA activity. NGF and other growth factors are generated within the
injured peripheral nerve tissue and are transported back to the injured neurons
within the time frame of the observed enhancements of axon regeneration by the
conditioning lesion. Such findings point toward the potential to exploit signaling
mechanisms of NGF and other growth factors to facilitate repair in the CNS.
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Inappropriate Connectivity It is important to consider that increases in NGF and

other growth factors after injury may stimulate formation of inappropriate connections and concomitant unwanted side effects. For example, after experimental
spinal cord injury, endogenous NGF-induced sprouting of small-diameter afferent
fibers has been implicated as a primary cause of autonomic dysreflexia (Krenz et al
1999), an important clinical problem of patients with spinal cord injury. Thus, not
all fiber regeneration and connectivity triggered by NGF and other growth factors
after injury may be beneficial, and aberrant and inappropriate pathways may also
be formed. Such possibilities must be studied and understood before treatment
strategies are considered.
FAILURE OF NGF SIGNALING AND

NEURODEGENERATION
Early ideas about the functions of NGF and other members of the neurotrophin
family naturally focused on their roles as neuronal survival factors (Barde 1989).
Strict interpretation of the neurotrophic hypothesis led to the suggestion that neurons might be dependent on a continuous, constitutive supply of a single targetderived neurotrophin not only during development but throughout adult life and
aging. An obvious extension of this idea is that an interruption in this continuously
required supply of target-derived neurotrophic support might be a direct cause
of neuronal death in aging and degenerative disease. Evidence accumulated to
date has not substantiated this idea. As discussed above, developmentally NGFdependent neurons for the most part become independent of a constitutive supply
of target-derived NGF for acute survival once they have established their connections and reached maturity. In addition, there is no evidence for a decline in
NGF production in aging or degenerative disease; neither NGF mRNA nor protein
are reduced in the cerebral cortex of aged animals (Alberch et al 1991, Crutcher
& Weingartner 1991) or patients with Alzheimers disease, where NGF protein
levels may even be increased (Crutcher et al 1993, Goedert et al 1986, Scott et al
1995). These observations do not, however, preclude other effects precipitated by
an aging- or disease-related failure of NGF signaling, and there is evidence that
failure of NGF signaling contributes to certain neurodegenerative processes.
NGF and the Age-Related Atrophy and Vulnerability

of Forebrain Cholinergic Neurons
TrkA and p75NTR expressing basal forebrain cholinergic neurons undergo moderate degenerative changes in aging, including cell atrophy, downregulation of
transmitter-synthesizing enzyme, and mild cell loss in both animals and humans,
and these degenerative changes are markedly exacerbated in Alzheimers disease
(de Lacalle et al 1991a,b; Finch 1993; Fischer et al 1987, 1991; Pearson et al 1983;
Whitehouse et al 1982). With the exception of cell loss, such atrophic changes
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can also be subacutely induced in young adult animals by disrupting access of

these neurons to their target cells, which produce NGF and other neurotrophins
(Kordower et al 1993; Sofroniew et al 1990, 1993). Furthermore, atrophic changes
can be reversed in aged animals by infusions of exogenous NGF (Fischer et al
1987). These findings suggest that failure of neurotrophin signaling may underlie
or contribute to the atrophic neuronal changes observed in aging or degenerative
disease. However, as described above, most studies agree that NGF levels are not
substantially reduced in aging or Alzheimers disease. Alternatively, available evidence does suggest that intrinsic neuronal changes might compromise the ability
of aged basal forebrain cholinergic neurons to derive neurotrophic support. In aged
rats, forebrain cholinergic neurons exhibit a reduced capacity for generalized retrograde transport and a pronounced reduction specifically in the retrograde transport
of NGF; cholinergic neurons that do not transport NGF are severely shrunken and
downregulate TrkA expression (Cooper et al 1994, de Lacalle et al 1996). Even
though NGF protein levels are not reduced in the cortex, they are substantially reduced in the basal forebrain of aged animals and patients with Alzheimers disease
(Alberch et al 1991, Scott et al 1995), as well as in mice with Downs syndrome
(JC Cooper, A Salehi, P Belichenko, J-D Delcroix, J Chua-Couzens, J Kilbridge,
CL Howe, WC Mobley, submitted for publication). These findings all suggest
a disturbance in retrograde transport and NGF signaling mechanisms in these neurons in aging and Alzheimers disease. Age-related declines of axonal transport
have been reported in other neuronal systems, such as sciatic nerve (McMartin
& OConnor 1979), and disturbances in neurofilaments and axonal transport have
been proposed as a possible mechanism contributing to neurodegenerative changes
associated with aging and such age-related CNS diseases as Alzheimers disease
(Gadjusek 1985, Saper et al 1987). Abnormal phosphorylation of the microtubuleassociated protein Tau is the basis for the formation of tangles in aged neurons
(Goedert 1996), and forebrain cholinergic neurons exhibit tangle formation in
aging and Alzheimers disease, with likely disruption of microtubule-dependent
axonal transport.
Taken together, these observations suggest that an intrinsic, age-related reduction in the capacity of basal forebrain cholinergic neurons to sustain retrograde
NGF signaling may contribute to the degenerative changes seen in basal forebrain
cholinergic neurons in aging that is markedly exacerbated in Alzheimers disease.
Basal forebrain cholinergic neurons may be exquisitely sensitive to interruptions
in NGF signaling as a by-product of the positive feedback in NGF signaling discussed above, such that an initially small failure in NGF signaling may be rapidly
exacerbated by downregulation of NGF receptors and other changes (Sofroniew &
Mobley 1993). The consequences of this failure in NGF signaling may be both
direct, by inducing cellular atrophy and changes in gene expression, and indirect, by increasing the vulnerability of the atrophic neurons to other insults, such
as glutamate signaling, which may become excitotoxic in the absence of NGF
signaling. As discussed above, recent studies have shown NGF significantly attenuates glutamate receptormediated death of forebrain cholinergic neurons, and
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that aged rats with reduced capacity to retrogradely transport NGF exhibit significantly increased vulnerability of cholinergic neurons to glutamate toxicity. These
findings suggest that endogenous NGF serves neuroprotective functions, and that
loss of target-derived NGF signaling, by increasing vulnerability to excitotoxicity,
may contribute to the gradual loss of basal forebrain cholinergic neurons in aging
and Alzheimers disease. The potential for failure of neuroprotective mechanisms
provided by endogenous growth factor signaling to cause or exacerbate neurodegeneration is not widely considered in the context of mechanisms that may be
operant in neurodegeneration. A better understanding of such mechanisms may
facilitate the development of protective interventions.
NGF SIGNALING AND THERAPEUTIC INTERVENTION

The many potentially beneficial effects of NGF signaling in neural protection and
repair raise possibilities of therapeutic intervention using either NGF protein or
small-molecule analogues (LeSauteur et al 1996, Longo & Mobley 1996, Yuen &
Mobley 1996). Nevertheless, the diversity of cells that respond to NGF signaling
may predispose to unwanted side effects when NGF or NGF agonists/antagonists
are delivered systemically. For example, in a randomized and placebo-controlled
study on the safety of intravenous or subcutaneous administration of NGF, patients
experienced sustained hyperalgesia, which varied in a dose-dependent manner
(Petty et al 1994). Infusions of NGF into the cerebroventricular system also led to
a variety of undesirable and unwanted effects in patients and animals (EriksdotterJonhagen et al 1998, Winkler et al 2000). Thus, ways of achieving site-specific
delivery or identifying means of achieving cell-type selective activation of NGF
receptors, or of NGF signalling pathways, may be needed to realize the therapeutic
potential that NGF signaling appears to hold.
The diversity of NGF-responsive cells also raises the possibility that NGF
signaling may, under certain circumstances, spill over from one cell compartment
to another, causing unwanted and undesirable effects, and may thus represent part
of a pathophysiological mechanism. For example, NGF produced and released
for signaling intended for regulation of neurons or inflammatory cells may affect
glia and present a potential means by which oligodendrocytes could be killed by
p75NTR-signaling. Such potential effects will need to be understood before there
are attempts to exploit NGF signaling for therapeutic interventions in the CNS.
Therapeutic trials must also be preceded by careful studies in realistic animal
models of disease or injury. Even when these steps have been completed and have
defined a role for NGF treatment, there is no guarantee of success in humans. The
recent phase III trial of NGF in diabetic neuropathy failed to show an effect of NGF.
This may well have resulted from the failure to deliver NGF in adequate amounts to
sensory neurons, a consequence of the fact that pain limited the NGF dose that could
be given. These and other factors will need to be addressed before NGF or NGF
analogues can be successfully used to intervene in neurodegenerative diseases.
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CONCLUSIONS
Growth factors play important roles as intercellular signaling molecules throughout
development, adult life, and aging. Many growth factors influence a wide range
of cell types and take part in numerous functions. NGF is no exception, and ideas
about its functions have steadily expanded. In addition to its long-recognized
developmental effects on the survival and maturation of a few restricted neuronal
populations in the PNS and CNS, NGF has effects on numerous types of neurons
and nonneuronal cells throughout adult life and during aging. Among its different
functions, NGF signaling appears to play important roles in the response to injury
or disease that subserve neuroprotection and neural repair.
ACKNOWLEDGMENTS
The authors wish to acknowledge the support of the McGowan Charitable Trust,
the Adler Foundation, the Christopher Reeve Paralysis Foundation, and NIH Grant
NS24054. CL Howe is supported by a Howard Hughes Medical Institute Predoctoral Fellowship and the Adler Foundation. We also thank numerous colleagues
for discussions, information, and criticism, including J-D Delcroix, C-B Wu, P
Belichenko, A Salehi, J Valletta, S Lai, A Langer-Gould, and A Kruttgen.
Visit the Annual Reviews home page at www.AnnualReviews.org
LITERATURE CITED
Abiru Y, Katoh-Semba R, Nishio C, Hatanaka
H. 1998. High potassium enhances secretion
of neurotrophic factors from cultured astrocytes. Brain Res. 809:11526
Agerman K, Canlon B, Duan M, Ernfors P.
1999. Neurotrophins, NMDA receptors, and
nitric oxide in development and protection
of the auditory system. Ann. NY Acad. Sci.
884:13142
Alberch J, Perez-Navarro E, Arenas E, Marsal J.
1991. Involvement of nerve growth factor and
its receptor in the regulation of the cholinergic function in aged rats. J. Neurochem.
57:148387
Alema S, Casalbore P, Agostini E, Tato F.
1985. Differentiation of PC12 phaeochromocytoma cells induced by v-src oncogene. Nature 316:5579
Alessi DR, Caudwell FB, Andjelkovic M, Hemmings BA, Cohen P. 1996. Molecular basis
for the substrate specificity of protein kinase
B; comparison with MAPKAP kinase-1 and

p70 S6 kinase. FEBS Lett. 399:33338
Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, et al. 1997a. 3-Phosphoinositide-dependent protein kinase-1
(PDK1): structural and functional homology
with the Drosophila DSTPK61 kinase. Curr.
Biol. 7:77689
Alessi DR, James SR, Downes CP, Holmes AB,
Gaffney PR, et al. 1997b. Characterization
of a 3-phosphoinositide-dependent protein
kinase which phosphorylates and activates
protein kinase Balpha. Curr. Biol. 7:261
69
Aloe L. 1987. Intracerebral pretreatment with
nerve growth factor prevents irreversible
brain lesions in neonatal rats injected with
ibotenic acid. Biotechnology 5:108586
Aloe L. 1998. Nerve growth factor and autoimmune diseases: role of tumor necrosis factoralpha. Adv. Pharmacol. 42:59194
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


Altar CA, Dugich-Djordjevic M, Armanini
M, Bakhit C. 1991. Medial-to-lateral gradient of neostriatal NGF receptors: relationship to cholinergic neurons and NGFlike immunoreactivity. J. Neurosci. 11:828
36
Andjelkovic M, Jakubowicz T, Cron P, Ming
XF, Han JW, Hemmings BA. 1996. Activation and phosphorylation of a pleckstrin
homology domain containing protein kinase
(RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc. Natl. Acad.
Sci. USA 93:5699704
Angenstein F, Greenough WT, Weiler IJ. 1998.
Metabotropic glutamate receptor-initiated
translocation of protein kinase p90rsk to
polyribosomes: a possible factor regulating
synaptic protein synthesis. Proc. Natl. Acad.
Sci. USA 95:1507883
Anton ES, Weskamp G, Reichardt LF, Matthew
WD. 1994. Nerve growth factor and its lowaffinity receptor promote Schwann cell migration. Proc. Natl. Acad. Sci. USA 91:2795
99
Arch RH, Gedrich RW, Thompson CB. 1998.
Tumor necrosis factor receptor-associated
factors (TRAFs)a family of adapter proteins that regulates life and death. Genes Dev.
12:282130
Arendt T, Bruckner MK, Krell T, Pagliusi S,
Kruska L, Heumann R. 1995. Degeneration
of rat cholinergic basal forebrain neurons and
reactive changes in nerve growth factor expression after chronic neurotoxic injury. II.
Reactive expression of the nerve growth factor gene in astrocytes. Neuroscience 65:647
59
Asaoka Y, Oka M, Yoshida K, Sasaki Y,
Nishizuka Y. 1992. Role of lysophosphatidylcholine in T-lymphocyte activation:
involvement of phospholipase A2 in signal
transduction through protein kinase C. Proc.
Natl. Acad. Sci. USA 89:644751
Bamji SX, Majdan M, Pozniak CD, Belliveau
DJ, Aloyz R, et al. 1998. The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occur-
1257
ring sympathetic neuron death. J. Cell Biol.

140:91123
Bar-Sagi D, Feramisco JR. 1985. Microinjection of the ras oncogene protein into PC12
cells induces morphological differentiation.
Cell 42:84148
Barde YA. 1989. Trophic factors and neuronal
survival. Neuron 2:152534
Barker PA, Shooter EM. 1994. Disruption of
NGF binding to the low affinity neurotrophin
receptor p75LNTR reduces NGF binding to
TrkA on PC12 cells. Neuron 13:20315
Barouch R, Appel E, Kazimirsky G, Braun A,
Renz H, Brodie C. 2000. Differential regulation of neurotrophin expression by mitogens and neurotransmitters in mouse lymphocytes. J. Neuroimmunol. 103:11221
Barrett GL, Bartlett PF. 1994. The p75 nerve
growth factor receptor mediates survival or
death depending on the stage of sensory neuron development. Proc. Natl. Acad. Sci. USA
91:65015
BartLett SE, Reynolds AJ, Weible M, Heydon
K, Hendry IA. 1997. In sympathetic but not
sensory neurones, phosphoinositide-3 kinase
is important for NGF-dependent survival and
the retrograde transport of 125I-NGF. Brain
Res. 761:25762
Basu T, Warne PH, Downward J. 1994. Role
of Shc in the activation of Ras in response
to epidermal growth factor and nerve growth
factor. Oncogene 9:348391
Bausenwein BS, Schmidt M, Mielke B, Raabe
T. 2000. In vivo functional analysis of the
daughter of sevenless protein in receptor tyrosine kinase signaling. Mech. Dev. 90:205
15
Bazan JF. 1990. Structural design and molecular evolution of a cytokine receptor superfamily. Proc. Natl. Acad. Sci. USA 87:69348
Beattie EC, Howe CL, Wilder A, Brodsky FM,
Mobley WC. 2001. NGF signals through
TrkA to increase clathrin at the plasma membrane and enhance clathrin-mediated membrane trafficking. J. Neurosci. In press
Bell RM, Burns DJ. 1991. Lipid activation of
protein kinase C. J. Biol. Chem. 266:466164
P1: GDL
April 13, 2001

1258
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
Benedetti M, Levi A, Chao MV. 1993. Differential expression of nerve growth factor receptors leads to altered binding affinity and neurotrophin responsiveness. Proc. Natl. Acad.
Sci. USA 90:785963
Berg-von der Emde K, Dees WL, Hiney JK,
Hill D, Dissen GA, et al. 1995. Neurotrophins and the neuroendocrine brain:
different neurotrophins sustain anatomically
and functionally segregated subsets of hypothalamic dopaminergic neurons. J. Neurosci. 15:422337
Berkemeier LR, Winslow JW, Kaplan DR,
Nikolics K, Goeddel DV, Rosenthal A. 1991.
Neurotrophin-5: a novel neurotrophic factor
that activates trk and trkB. Neuron 7:85766
Berkowitz LA, Riabowol KT, Gilman MZ.
1989. Multiple sequence elements of a single
functional class are required for cyclic AMP
responsiveness of the mouse c-fos promoter.
Mol. Cell. Biol. 9:427281
Berninger B, Poo M. 1996. Fast actions of
neurotrophic factors. Curr. Opin. Neurobiol.
6:32430
Berra E, Diaz-Meco MT, Dominguez I, Municio MM, Sanz L, et al. 1993. Protein kinase
C zeta isoform is critical for mitogenic signal
transduction. Cell 74:55563
Berra E, Diaz-Meco MT, Lozano J, Frutos S,
Municio MM, et al. 1995. Evidence for a
role of MEK and MAPK during signal transduction by protein kinase C zeta. EMBO J.
14:615763
Berzaghi MP, Cooper JD, Castren E, Zafra F,
Sofroniew MV, et al. 1993. Cholinergic regulation of brain-derived neurotrophic factor
(BDNF) and nerve growth factor (NGF) but
not neurotrophin-3 (NT-3) mRNA levels in
the developing rat hippocampus. J. Neurosci.
13:381826
Bibel M, Hoppe E, Barde YA. 1999. Biochemical and functional interactions between
the neurotrophin receptors trk and p75NTR.
EMBO J. 18:61622
Bilderback TR, Gazula VR, Lisanti MP, Dobrowsky RT. 1999. Caveolin interacts with
Trk A and p75(NTR) and regulates neu-
rotrophin signaling pathways. J. Biol. Chem.

274:25763
Bilderback TR, Grigsby RJ, Dobrowsky
RT. 1997. Association of p75(NTR) with
caveolin and localization of neurotrophininduced sphingomyelin hydrolysis to caveolae. J. Biol. Chem. 272:1092227
Birren SJ, Lo L, Anderson DJ. 1993. Sympathetic neuroblasts undergo a developmental
switch in trophic dependence. Development
119:597610
Bizon JL, Lauterborn JC, Gall CM. 1999. Subpopulations of striatal interneurons can be
distinguished on the basis of neurotrophic
factor expression. J. Comp. Neurol. 408:283
98
Boise LH, Gottschalk AR, Quintans J, Thompson CB. 1995. Bcl-2 and Bcl-2-related proteins in apoptosis regulation. Curr. Top. Microbiol. Immunol. 200:10721
Boldin MP, Mett IL, Varfolomeev EE, Chumakov I, Shemer-Avni Y, et al. 1995a. Selfassociation of the death domains of the
p55 tumor necrosis factor (TNF) receptor and
Fas/APO1 prompts signaling for TNF and
Fas/APO1 effects. J. Biol. Chem. 270:387
91
Boldin MP, Varfolomeev EE, Pancer Z, Mett
IL, Camonis JH, Wallach D. 1995b. A novel
protein that interacts with the death domain
of Fas/APO1 contains a sequence motif related to the death domain. J. Biol. Chem. 270:
779598
Boniece I, Wagner J. 1993. Growth factors
protect PC12 cells against ischemia by a
mechanism that is independent of PKA,
PKC, and protein synthesis. J. Neurosci. 13:
4220
Bonini S, Lambiase A, Bonini S, Levi-Schaffer
F, Aloe L. 1999. Nerve growth factor: an
important molecule in allergic inflammation
and tissue remodelling. Int. Arch. Allergy Immunol. 118:15962
Bonni A, Ginty DD, Dudek H, Greenberg ME.
1995. Serine 133-phosphorylated CREB
induces transcription via a cooperative
mechanism that may confer specificity to
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


neurotrophin signals. Mol. Cell. Neurosci.
6:16883
Bothwell M. 1995. Functional interactions of
neurotrophins and neurotrophin receptors.
Annu. Rev. Neurosci. 18:22353
Brann AB, Scott R, Neuberger Y, Abulafia D,
Boldin S, et al. 1999. Ceramide signaling
downstream of the p75 neurotrophin receptor
mediates the effects of nerve growth factor on
outgrowth of cultured hippocampal neurons.
J. Neurosci. 19:8199206
Bredesen DE, Rabizadeh S. 1997. p75NTR
and apoptosis: Trk-dependent and Trkindependent effects. Trends Neurosci. 20:
28790
Brennan C, Rivas-Plata K, Landis SC. 1999.
The p75 neurotrophin receptor influences
NT-3 responsiveness of sympathetic neurons
in vivo. Nat. Neurosci. 2:699705
Brown MT, Cooper JA. 1996. Regulation, substrates and functions of src. Biochim. Biophys. Acta 1287:12149
Burgering BM, Coffer PJ. 1995. Protein kinase
B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376:599
602
Bush TG, Puvanachandra N, Horner CH, Polito
A, Ostenfeld T, et al. 1999. Leukocyte infiltration, neuronal degeneration and neurite
outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice.
Neuron 23:297308
Butte MJ, Hwang PK, Mobley WC, Fletterick
RJ. 1998. Crystal structure of neurotrophin3 homodimer shows distinct regions are used
to bind its receptors. Biochemistry 37:16846
52
Cacace AM, Ueffing M, Philipp A, Han EK,
Kolch W, Weinstein IB. 1996. PKC epsilon
functions as an oncogene by enhancing activation of the Raf kinase. Oncogene 13:2517
26
Cai D, Shen Y, De Bellard ME, Tang S, Filbin
MT. 1999. Prior exposure to neurotrophins
blocks the inhibition of axonal regeneration
by MAG and myelin via a cAMP-dependent
mechanism. Neuron 22:89101
1259
Campenot RB. 1977. Local control of neurite

development by nerve growth factor. Proc.
Cance WG, Craven RJ, Bergman M, Xu L, Alitalo K, Liu ET. 1994. Rak, a novel nuclear
tyrosine kinase expressed in epithelial cells.
Cell Growth Differ. 5:134755
Cao Z, Henzel WJ, Gao X. 1996a. IRAK: a
kinase associated with the interleukin-1 receptor. Science 271:112831
Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV. 1996b. TRAF6 is a signal transducer
for interleukin-1. Nature 383:44346
Carlson N, Wieggel W, Chen J, Bacchi A,
Rogers S, Gahring L. 1999. Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNFalpha impart neuroprotection to an excitotoxin through distinct pathways. J. Immunol.
163:396368
Carroll MP, May WS. 1994. Protein kinase Cmediated serine phosphorylation directly activates Raf-1 in murine hematopoietic cells.
J. Biol. Chem. 269:124956
Carter BD, Kaltschmidt C, Kaltschmidt B, Offenhauser N, Bohm-Matthaei R, et al. 1996.
Selective activation of NF-kappa B by nerve
growth factor through the neurotrophin receptor p75. Science 272:54245
Carter BD, Lewin GR. 1997. Neurotrophins
live or let die: does p75NTR decide? Neuron 18:18790
Casaccia-Bonnefil P, Carter BD, Dobrowsky
RT, Chao MV. 1996. Death of oligodendrocytes mediated by the interaction of nerve
growth factor with its receptor p75. Nature
383:71619
Casademunt E, Carter BD, Benzel I, Frade JM,
Dechant G, Barde YA. 1999. The zinc finger
protein NRIF interacts with the neurotrophin
receptor p75(NTR) and participates in
programmed cell death. EMBO J. 18:6050
61
Casey PJ. 1995. Mechanisms of protein prenylation and role in G protein function.
Biochem. Soc. Trans. 23:16166
Cellerino A. 1995. Expression of messenger
RNA coding for the nerve growth factor
P1: GDL
April 13, 2001

1260
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
receptor trkA in the hippocampus of the adult

rat. Neuroscience 70:61316
Cellerino A, Maffei L. 1996. The action of neurotrophins in the development and plasticity
of the visual cortex. Prog. Neurobiol. 49:53
71
Chao M, Casaccia-Bonnefil P, Carter B, Chittka A, Kong H, Yoon SO. 1998. Neurotrophin
receptors: mediators of life and death. Brain
Res. Rev. 26:295301
Chen KS, Nishimura MC, Armanini MP, Crowley C, Spencer SD, Phillips HS. 1997.
Disruption of a single allele of the nerve
growth factor gene results in atrophy of basal
forebrain cholinergic neurons and memory
deficits. J. Neurosci. 17:728896
Chen RH, Sarnecki C, Blenis J. 1992. Nuclear localization and regulation of erk- and
rsk-encoded protein kinases. Mol. Cell. Biol.
12:91527
Cheng B, Mattson MP. 1991. NGF and bFGF
protect rat hippocampal and human cortical neurons against hypoglycemic damage
by stabilizing calcium homeostasis. Neuron
7:103141
Chou MM, Hou W, Johnson J, Graham LK, Lee
MH, et al. 1998. Regulation of protein kinase
C zeta by PI 3-kinase and PDK-1. Curr. Biol.
8:106977
Chrivia JC, Kwok RP, Lamb N, Hagiwara M,
Montminy MR, Goodman RH. 1993. Phosphorylated CREB binds specifically to the
nuclear protein CBP. Nature 365:85559
Cifone MG, De Maria R, Roncaioli P, Rippo
MR, Azuma M, et al. 1994. Apoptotic signaling through CD95 (Fas/Apo-1) activates
an acidic sphingomyelinase. J. Exp. Med.
180:154752
Clary DO, Reichardt LF. 1994. An alternatively
spliced form of the nerve growth factor receptor TrkA confers an enhanced response
to neurotrophin 3. Proc. Natl. Acad. Sci. USA
91:1113337
Cohen P, Alessi DR, Cross DA. 1997. PDK1,
one of the missing links in insulin signal
transduction? FEBS Lett. 410:310
Cohen-Cory S, Dreyfus CF, Black IB. 1991.
NGF and excitatory neurotransmitters regulate survival and morphogenesis of cultured cerebellar Purkinje cells. J. Neurosci.
11:46271
Coleman ES, Wooten MW. 1994. Nerve growth
factor-induced differentiation of PC12 cells
employs the PMA-insensitive protein kinase
C-zeta isoform. J. Mol. Neurosci. 5:3957
Conover JC, Yancopoulos GD. 1997. Neurotrophin regulation of the developing nervous system: analyses of knockout mice. Rev.
Neurosci. 8:1327
Cooper JD, Lindholm D, Sofroniew MV. 1994.
Reduced transport of 125I-NGF by cholinergic neurons and downregulated TrkA expression in the medial septum of aged rats.
Neuroscience 62:62529
Cosman D, Lyman SD, Idzerda RL, Beckmann
MP, Park LS, et al. 1990. A new cytokine
receptor superfamily. Trends Biochem. Sci.
15:26570
Coulson EJ, Reid K, Baca M, Shipham KA,
Hulett SM, et al. 2001. Chopper, a new death
domain of the p75 neurotrophin receptor that
mediates rapid neuronal cell death. J. Biol.
Chem. In press
Cowley S, Paterson H, Kemp P, Marshall CJ.
1994. Activation of MAP kinase kinase is
necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3
cells. Cell 77:84152
Crews CM, Alessandrini A, Erikson RL. 1992.
Erks: their fifteen minutes has arrived. Cell
Growth Differ. 3:13542
Crews CM, Erikson RL. 1992. Purification
of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the
Erk-1 gene product: relationship to the fission
yeast byr1 gene product. Proc. Natl. Acad.
Sci. USA 89:82059
Crowder RJ, Freeman RS. 1998. Phosphatidylinositol 3-kinase and Akt protein kinase are
necessary and sufficient for the survival of
nerve growth factor-dependent sympathetic
neurons. J. Neurosci. 18:293343
Crowley C, Spencer SD, Nishimura MC, Chen
KS, Pitts-Meek S, et al. 1994. Mice lacking
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


nerve growth factor display perinatal loss
of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons.
Cell 76:100111
Crutcher KA, Scott SA, Liang S, Everson WV,
Weingartner J. 1993. Detection of NGF-like
activity in human brain tissue: increased
levels in Alzheimers disease. J. Neurosci.
13:254050
Crutcher KA, Weingartner J. 1991. Hippocampal NGF levels are not reduced in the aged
fischer 344 rat. Neurobiol. Aging 12:44954
Cuello AC. 1994. Trophic factor therapy in the
adult CNS: remodelling of injured basalocortical neurons. Prog. Brain Res. 100:213
21
Cuello AC. 1996. Effects of trophic factors on
the CNS cholinergic phenotype. Prog. Brain
Res. 109:34758
Culmsee C, Semkova I, Krieglstein J. 1999.
NGF mediates the neuroprotective effect of
the 2-adrenoceptor agonist clenbuterol in
vitro and in vivo: evidence from an NGFantisense study. Neurochem. Int. 35:4757
Cunha GMA, Moraes RA, Moraes GA, Franca
MC Jr, Moraes MO, Viana GSB. 1998. Nerve
growth factor, ganglioside and vitamin E reverse glutamate cytotoxicity in hippocampal
cells. Eur. J. Pharmacol. 367:10712
Cunningham ME, Stephens RM, Kaplan DR,
Greene LA. 1997. Autophosphorylation of
activation loop tyrosines regulates signaling
by the TRK nerve growth factor receptor. J.
Biol. Chem. 272:1095767
Datta K, Bellacosa A, Chan TO, Tsichlis
PN. 1996. Akt is a direct target of the
phosphatidylinositol 3-kinase. Activation by
growth factors, v-src and v-Ha-ras, in Sf9 and
mammalian cells. J. Biol. Chem. 271:30835
39
Datta SR, Brunet A, Greenberg ME. 1999. Cellular survival: a play in three Akts. Genes
Dev. 13:290527
Datta SR, Dudek H, Tao X, Masters S, Fu H,
et al. 1997. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death
machinery. Cell 91:23141
1261
Davies AM. 1994. The role of neurotrophins in

the developing nervous system. J. Neurobiol.
25:133448
Davies SW, Beardsall K. 1992. Nerve growth
factor selectively prevents excitotoxin induced degeneration of striatal cholinergic
neurons. Neurosci. Lett. 140:16164
Debeir T, Saragovi HU, Cuello AC. 1999. A
nerve growth factor mimetic TrkA antagonist causes withdrawal of cortical cholinergic boutons in the adult rat. Proc. Natl. Acad.
Sci. USA 96:406772
Dechant G, Barde YA. 1997. Signalling through
the neurotrophin receptor p75NTR. Curr.
Opin. Neurobiol. 7:41318
de Lacalle S, Cooper JD, Svendsen CN, Dunnett SB, Sofroniew MV. 1991a. Degenerative changes in basal forebrain cholinergic
neurons in aged rats. A quantitative analysis
of cells stained for ChAT or NGFr, or retrogradely labelled with fluorescent tracer. Soc.
Neurosci. Abstr. 17:1508
de Lacalle S, Cooper JD, Svendsen CN, Dunnett SB, Sofroniew MV. 1996. Reduced
retrograde labeling with fluorescent tracer accompanies neuronal atrophy of basal forebrain cholinergic neurons in aged rats. Neuroscience 75:1927
de Lacalle S, Iraizoz I, Gonzalo LM. 1991b. Differential changes in cell size and number in
topographic subdivisions of human basal nucleus in normal aging. Neuroscience 43:445
56
del Peso L, Gonzalez-Garcia M, Page C,
Herrera R, Nunez G. 1997. Interleukin-3induced phosphorylation of BAD through the
protein kinase Akt. Science 278:68789
Derby A, Engleman VW, Frierdich GE, Neises
G, Rapp SR, Roufa DG. 1993. Nerve growth
factor facilitates regeneration across nerve
gaps: morphological and behavioral studies
in rat sciatic nerve. Exp. Neurol. 119:176
91
Dmitrieva N, Shelton D, Rice A, McMahon
S. 1997. The role of nerve growth factor in
a model of visceral inflammation. Neurosci.
78:44959
P1: GDL
April 13, 2001

1262
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
Dobrowsky RT, Jenkins GM, Hannun YA.

1995. Neurotrophins induce sphingomyelin
hydrolysis. Modulation by co-expression of
p75NTR with Trk receptors. J. Biol. Chem.
270:2213542
Dobrowsky RT, Werner MH, Castellino AM,
Chao MV, Hannun YA. 1994. Activation
of the sphingomyelin cycle through the
low-affinity neurotrophin receptor. Science
265:159699
Dougherty K, Milner T. 1999. p75NTR immunoreactivity in the rat dentate gyrus is
mostly within presynaptic profiles but is also
found in some astrocytic and postsynaptic
profiles. J. Comp. Neurol. 407:7791
Douville E, Downward J. 1997. EGF induced
SOS phosphorylation in PC12 cells involves
P90 RSK-2. Oncogene 15:37383
Dudek H, Datta SR, Franke TF, Birnbaum MJ,
Yao R, et al. 1997. Regulation of neuronal
survival by the serine-threonine protein kinase Akt. Science 275:66165
Dugan LL, Creedon DJ, Johnson EM, Holtzman
DM. 1997. Rapid suppression of free radical
formation by nerve growth factor involves
the mitogen-activated protein kinase pathway. Proc. Natl. Acad. Sci. USA 94:4086
91
Easton RM, Deckwerth TL, Parsadanian AS,
Johnson EM Jr. 1997. Analysis of the mechanism of loss of trophic factor dependence
associated with neuronal maturation: a phenotype indistinguishable from bax deletion.
J. Neurosci. 17:965666
Eckenstein F. 1988. Transient expression
of NGF-receptor-like immunoreactivity in
postnatal rat brain and spinal cord. Brain Res.
446:14954
Edwards RH, Selby MJ, Mobley WC, Weinrich
SL, Hruby DE, Rutter WJ. 1988. Processing
and secretion of nerve growth factor: expression in mammalian cells with a vaccinia virus
vector. Mol. Cell. Biol. 8:245664
Edwards RH, Selby MJ, Rutter WJ. 1986.
Differential RNA splicing predicts two distinct nerve growth factor precursors. Nature
319:78487
Elkabes S, DiCicco-Bloom E, Black I. 1996.

Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J. Neurosci. 16:250821
Elkabes S, Peng L, Black IB. 1998.
Lipopolysaccharide differentially regulates
microglial trk receptor and neurotrophin
expression. J. Neurosci. Res. 54:11722
Ellinger-Ziegelbauer H, Brown K, Kelly K,
Siebenlist U. 1997. Direct activation of the
stress-activated protein kinase (SAPK) and
extracellular signal-regulated protein kinase
(ERK) pathways by an inducible mitogenactivated protein kinase/ERK kinase kinase 3 (MEKK) derivative. J. Biol. Chem.
272:266874
Enokido Y, Wyatt S, Davies AM. 1999. Developmental changes in the response of trigeminal neurons to neurotrophins: influence of
birthdate and the ganglion environment. Development 126:436573
Eriksdotter-Jonhagen M, Nordberg A, Amberla
K, Backman L, Ebendal T, et al. 1998. Intracerebroventricular infusion of nerve growth
factor in three patients with Alzheimers disease. Dement. Geriatr. Cogn. Disord. 9:246
57
Erikson E, Maller JL. 1991. Purification and
characterization of ribosomal protein S6 kinase I from Xenopus eggs. J. Biol. Chem.
266:524955
Erikson E, Maller JL, Erikson RL. 1991. Xenopus ribosomal protein S6 kinase II. Methods
Enzymol. 200:25268
Ernfors P, Hallbook F, Ebendal T, Shooter EM,
Radeke MJ, et al. 1988. Developmental and
regional expression of beta-nerve growth factor receptor mRNA in the chick and rat. Neuron 1:98396
Ernfors P, Henschen A, Olson L, Persson H.
1989. Expression of nerve growth factor
receptor mRNA is developmentally regulated
and increased after axotomy in rat spinal cord
motoneurons. Neuron 2:160513
Erpel T, Courtneidge SA. 1995. Src family
protein tyrosine kinases and cellular signal
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


transduction pathways. Curr. Opin. Cell Biol.
7:17682
Facchinetti F, Dawson VL, Dawson TM. 1998.
Free radicals as mediators of neuronal injury.
Cell. Mol. Neurobiol. 18:60920
Fagan AM, Garber M, Barbacid M, SilosSantiago I, Holtzman DM. 1997. A role for
TrkA during maturation of striatal and basal
forebrain cholinergic neurons in vivo. J. Neurosci. 17:764454
Fahnestock M, Woo JE, Lopez GA, Snow
J, Walz DA, et al. 1991. beta-NGFendopeptidase: structure and activity of a
kallikrein encoded by the gene mGK-22. Biochemistry 30:344350
Finch CE. 1993. Neuron atrophy during aging:
programmed or sporadic. Trends Neurosci.
16:10410
Fischer W, Chen KS, Gage FH, Bjorklund A.
1991. Progressive decline in spatial learning
and integrity of forebrain cholinergic neurons
in rats during aging. Neurobiol. Aging 13:9
23
Fischer W, Wictorin K, Bjorklund A, Williams
LR, Varon S, Gage FH. 1987. Amelioration
of cholinergic neuronal atrophy and spatial
memory impairment in aged rats by nerve
growth factor. Nature 329:6568
Frade J, Barde Y. 1998. Microglia-derived nerve
growth factor causes cell death in the developing retina. Neuron 20:3541
Frade JM, Rodriguez-Tebar A, Barde Y. 1996.
Induction of cell death by endogenous nerve
growth factor through its p75 receptor. Nature 383:16668
Franke TF, Kaplan DR, Cantley LC. 1997.
PI3K: downstream AKTion blocks apoptosis. Cell 88:43537
Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, et al. 1995. The protein kinase encoded by the Akt proto-oncogene is a target
of the PDGF-activated phosphatidylinositol
3-kinase. Cell 81:72736
Freed E, Symons M, Macdonald SG, McCormick F, Ruggieri R. 1994. Binding of 143-3 proteins to the protein kinase Raf and effects on its activation. Science 265:171316
1263
French SJ, Humby T, Horner CH, Sofroniew

MV, Rattray M. 1999. Hippocampal neurotrophin and trk receptor mRNA levels are
altered by local administration of nicotine,
carbachol and pilocarpine. Mol. Brain Res.
67:12436
Friedman WJ, Greene LA. 1999. Neurotrophin
signaling via Trks and p75. Exp. Cell Res.
253:13142
Friedman WJ, Thakur S, Seidman L, Rabson
AB. 1996. Regulation of nerve growth factor mRNA by interleukin-1 in rat hippocampal astrocytes is mediated by NFB. J. Biol.
Chem. 271:3111520
Frim DM, Uhler TA, Short MP, Ezzedine ZD,
Klagsbrun M, et al. 1993. Effects of biologically delivered NGF, BDNF and bFGF
on striatal excitotoxic lesions. NeuroReport
4:36770
Frostick SP, Yin Q, Kemp GJ. 1998. Schwann
cells, neurotrophic factors, and peripheral
nerve regeneration. Microsurgery 18:397
405
Fu H, Xia K, Pallas DC, Cui C, Conroy K, et al.
1994. Interaction of the protein kinase Raf1 with 14-3-3 proteins. Science 266:126
29
Gadjusek DC. 1985. Hypothesis: interference
with axonal transport of neurofilament as a
common pathogenic mechanism in certain
diseases of the central nervous system. N.
Engl. J. Med. 312:71419
Gage FH, Batchelor P, Chen KS, Chin D, Higgins GA, et al. 1989. NGF receptor reexpression and NGF-mediated cholinergic neuronal
hypertrophy in the damaged adult neostriatum. Neuron 2:117784
Gall CM, Isackson PJ. 1989. Limbic seizures
increase neuronal production of messenger RNA for nerve growth factor. Science
245:75861
Gallo G, Lefcort FB, Letourneau PC. 1997. The
trkA receptor mediates growth cone turning
toward a localized source of nerve growth
factor. J. Neurosci. 17:544554
Gargano N, Levi A, Alema S. 1997. Modulation of nerve growth factor internalization by
P1: GDL
April 13, 2001

1264
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
direct interaction between p75 and TrkA receptors. J. Neurosci. Res. 50:112
Gee AP, Boyle MD, Munger KL, Lawman
MJ, Young M. 1983. Nerve growth factor:
stimulation of polymorphonuclear leukocyte
chemotaxis in vitro. Proc. Natl. Acad. Sci.
USA 80:721518
Gentry JJ, Casaccia-Bonnefil P, Carter BD.
2000. Nerve growth factor activation of nuclear factor B through its p75 receptor is an
anti-apoptotic signal in RN22 Schwannoma
cells. J. Biol. Chem. 275:755865
Gertler FB, Bennett RL, Clark MJ, Hoffmann
FM. 1989. Drosophila abl tyrosine kinase
in embryonic CNS axons: a role in axonogenesis is revealed through dosage-sensitive
interactions with disabled. Cell 58:103
13
Gertler FB, Hill KK, Clark MJ, Hoffmann
FM. 1993. Dosage-sensitive modifiers of
Drosophila abl tyrosine kinase function:
prospero, a regulator of axonal outgrowth,
and disabled, a novel tyrosine kinase substrate. Genes Dev. 7:44153
Ghoda L, Lin X, Greene WC. 1997. The 90kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of
IkappaBalpha and stimulates its degradation
in vitro. J. Biol. Chem. 272:2128188
Ghosh S, May MJ, Kopp EB. 1998. NF-kappa
B and Rel proteins: evolutionarily conserved
mediators of immune responses. Annu. Rev.
Immunol. 16:22560
Gille H, Kortenjann M, Thomae O, Moomaw C,
Slaughter C, et al. 1995. ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO J.
14:95162
Ginty DD, Bonni A, Greenberg ME. 1994.
Nerve growth factor activates a Rasdependent protein kinase that stimulates
c-fos transcription via phosphorylation of
CREB. Cell 77:71325
Goedert M, Fine A, Hunt SP, Ullrich A. 1986.
Nerve growth factor mRNA in peripheral and
central rat tissues and in the human central
nervous system: lesion effects in the rat brain
and levels in Alzheimers disease. Mol. Brain

Res. 1:8592
Goedert M. 1996. Tau protein and the neurofibrillary pathology of Alzheimers disease. Ann. NY Acad. Sci. 777:12131
Goss JR, OMalley ME, Zou L, Styren SD,
Kochanek PM, DeKosky ST. 1998. Astrocytes are the major souce of nerve growth
factor upregulation following traumatic brain
injury in the rat. Exp. Neurol. 149:3019
Gottlieb M, Matute C. 1999. Expression of
nerve growth factor in astrocytes of the hippocampal CA1 area following transient forebrain ischemia. Neuroscience 91:102734
Gotz R, Koster R, Winkler C, Raulf F, Lottspeich F, et al. 1994. Neurotrophin-6 is a new
member of the nerve growth factor family.
Nature 372:26669
Greene LA, Kaplan DR. 1995. Early events in
neurotrophin signalling via Trk and p75 receptors. Curr. Opin. Neurobiol. 5:57987
Greenberg ME, Hermanowski AL, Ziff EB.
1986. Effect of protein synthesis inhibitors
on growth factor activation of c-fos, c-myc,
and actin gene transcription. Mol. Cell. Biol.
6:105057
Greferath U, Bennie A, Kourakis A, BartLett
PF, Murphy M, Barrett GL. 2000. Enlarged
cholinergic forebrain neurons and improved
spatial learning in p75 knockout mice. Eur J.
Neurosci. 12:88593
Grimes ML, Beattie E, Mobley WC. 1997.
A signaling organelle containing the nerve
growth factor-activated receptor tyrosine kinase, TrkA. Proc. Natl. Acad. Sci. USA
94:990914
Grimes ML, Zhou J, Beattie EC, Yuen EC,
Hall DE, et al. 1996. Endocytosis of activated
TrkA: evidence that nerve growth factor induces formation of signaling endosomes. J.
Neurosci. 16:795064
Grinspan JB, Marchionni MA, Reeves M,
Coulaloglou M, Scherer SS. 1996. Axonal
interactions regulate Schwann cell apoptosis in developing peripheral nerve: neuregulin receptors and the role of neuregulins. J.
Neurosci. 16:610718
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


Gross A, Jockel J, Wei MC, Korsmeyer SJ.
1998. Enforced dimerization of BAX results
in its translocation, mitochondrial dysfunction and apoptosis. EMBO J. 17:387885
Gu C, Casaccia-Bonnefil P, Srinivasan A, Chao
MV. 1999. Oligodendrocyte apoptosis mediated by caspase activation. J. Neurosci.
19:304349
Gu H, Pratt JC, Burakoff SJ, Neel BG. 1998.
Cloning of p97/Gab2, the major SHP2binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced
gene activation. Mol. Cell 2:72940
Gu Q, Liu Y, Cynader MS. 1994. Nerve growth
factor-induced ocular dominance plasticity in
adult cat visual cortex. Proc. Natl. Acad. Sci.
USA 91:840812
Guegan C, Onteniente B, Makiura Y, MeradBoudia M, Ceballos-Picot I, Sola B. 1997.
Reduction of cortical infarction and impairment of apoptosis in NGF-transgenic mice
subjected to permanent focal ischemia. Mol.
Brain Res. 55:13340
Hadari YR, Kouhara H, Lax I, Schlessinger
J. 1998. Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast
growth factor-induced PC12 cell differentiation. Mol. Cell. Biol. 18:396673
Hagag N, Halegoua S, Viola M. 1986. Inhibition of growth factor-induced differentiation
of PC12 cells by microinjection of antibody
to ras p21. Nature 319:68082
Hakak Y, Hsu YS, Martin GS. 2000. Shp-2 mediates v-Src-induced morphological changes
and activation of the anti-apoptotic protein
kinase Akt. Oncogene 19:316471
Hasenohrl RU, Soderstrom S, Mohammed AH,
Ebendal T, Huston JP. 1997. Reciprocal
changes in expression of mRNA for nerve
growth factor and its receptors TrkA and
LNGFR in brain of aged rats in relation
to maze learning deficits. Exp. Brain Res.
114:20513
Hausser A, Storz P, Link G, Stoll H, Liu YC,
et al. 1999. Protein kinase C mu is negatively
regulated by 14-3-3 signal transduction proteins. J. Biol. Chem. 274:925864
1265
Hawley RJ, Scheibe RJ, Wagner JA. 1992.

NGF induces the expression of the VGF gene
through a cAMP response element. J. Neurosci. 12:257381
Heaton MB, Paiva M, Swanson DJ, Walker DW.
1993. Modulation of ethanol neurotoxicity
by nerve growth factor. Brain Res. 620:78
85
Heese K, Fiebich BL, Bauer J, Otten U.
1998. NF-B modulates lipopolysaccharideinduced microglial nerve growth factor expression. Glia 22:4017
Hefti F. 1986. Nerve growth factor promotes
survival of septal cholinergic neurons after
fimbrial transections. J. Neurosci. 6:215562
Heisenberg C-P, Cooper JD, Berke J, Sofroniew
MV. 1994. NMDA potentiates NGF-induced
sprouting of septal cholinergic neurons. NeuroReport 5:41316
Heumann R, Korsching S, Bandtlow C, Thoenen H. 1987a. Changes of nerve growth factor synthesis in nonneuronal cells in response
to sciatic nerve transection. J. Cell Biol.
104:162331
Heumann R, Lindholm D, Bandtlow C, Meyer
M, Radeke MJ, et al. 1987b. Differential
regulation of mRNA encoding nerve growth
factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc. Natl. Acad.
Sci. USA 84:873539
Hill CS, Marais R, John S, Wynne J, Dalton S,
Treisman R. 1993. Functional analysis of a
growth factor-responsive transcription factor
complex. Cell 73:395406
Holgado-Madruga M, Emlet DR, Moscatello
DK, Godwin AK, Wong AJ. 1996. A Grb2associated docking protein in EGF- and
insulin-receptor signalling. Nature 379:560
64
Holgado-Madruga M, Moscatello DK, Emlet DR, Dieterich R, Wong AJ. 1997.
Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the
promotion of cell survival by nerve growth
factor. Proc. Natl. Acad. Sci. USA 94:12419
24
P1: GDL
April 13, 2001

1266
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
Holtzman DM, Kilbridge J, Li Y, Cunningham

ET, Lenn NJ, et al. 1995. TrkA expression in
the CNS: evidence for the existence of several novel NGF-responsive CNS neurons. J.
Neurosci. 15:156776
Holtzman DM, Li Y, Parada LF, Kinsman S,
Chen CK, et al. 1992. p140trk mRNA marks
NGF-responsive forebrain neurons: evidence
that trk gene expression is induced by NGF.
Neuron 9:46578
Holtzman DM, Sheldon RA, Jaffe W, Cheng
Y, Ferriero DM. 1996. Nerve growth factor
protects the neonatal brain against hypoxicischemic injury. Ann. Neurol. 39:114
22
Horner CH, Lam HHD, Berke J, Cooper JD,
Sofroniew MV. 1999. Local and targetderived nerve growth factor protect basal
forebrain cholinergic neurons from glutamate receptor-mediated toxicity. Soc. Neurosci. Abstr. 25:770
Horvath CM, Wolven A, Machadeo D, Huber J,
Boter L, et al. 1993. Analysis of the trk NGF
receptor tyrosine kinase using recombinant
fusion proteins. J. Cell Sci. 17:22328
Howe CL, Mobley WC. 2001. Nerve growth
factor effects on cholinergic modulation of
hippocampal and cortical plasticity. In Neurobiology of the Neurotrophins, ed. I Mocchetti, FP Graham, pp. 255307
Huang CS, Zhou J, Feng AK, Lynch CC,
Klumperman J, et al. 1999. Nerve growth
factor signaling in caveolae-like domains
at the plasma membrane. J. Biol. Chem.
274:3670714
Huber LJ, Chao MV. 1995. A potential interaction of p75 and trkA NGF receptors revealed
by affinity crosslinking and immunoprecipitation. J. Neurosci. Res. 40:55763
Hutton L, deVellis J, Perez-Polo J. 1992.
Expression of p75NGFR TrkA, and TrkB
mRNA in Rat C6 glioma and type U astrocyte
cultures. J. Neurosci. Res. 32:37583
Hutton L, Perez-Polo J. 1995. In vitro glial responses to nerve growth factor. J. Neurosci.
Res. 41:18596
Ibanez CF. 1994. Structure function relation-
ships in the neurotrophin family. J. Neurobiol. 25:134961

Ibanez CF, Ebendal T, Barbany G, Murray-Rust
J, Blundell TL, Persson H. 1992. Disruption
of the low affinity receptor-binding site in
NGF allows neuronal survival and differentiation by binding to the trk gene product.
Cell 69:32941
Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ,
et al. 1993. Similarities and differences in the
way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells.
Neuron 10:13749
Irie K, Gotoh Y, Yashar BM, Errede B, Nishida
E, Matsumoto K. 1994. Stimulatory effects
of yeast and mammalian 14-3-3 proteins on
the Raf protein kinase. Science 265:171619
Jaiswal RK, Moodie SA, Wolfman A, Landreth
GE. 1994. The mitogen-activated protein
kinase cascade is activated by B-Raf in response to nerve growth factor through interaction with p21ras. Mol. Cell. Biol. 14:6944
53
Janknecht R, Ernst WH, Pingoud V, Nordheim
A. 1993. Activation of ternary complex factor
Elk-1 by MAP kinases. EMBO J. 12:5097
104
Jia M, Li M, Liu XW, Jiang H, Nelson
PG, Guroff G. 1999. Voltage-sensitive calcium currents are acutely increased by nerve
growth factor in PC12 cells. J. Neurophysiol.
82:284752
Jiang H, Takeda K, Lazarovici P, Katagiri Y, Yu
ZX, et al. 1999. Nerve growth factor (NGF)induced calcium influx and intracellular calcium mobilization in 3T3 cells expressing
NGF receptors. J. Biol. Chem. 274:26209
16
Joel PB, Smith J, Sturgill TW, Fisher TL,
Blenis J, Lannigan DA. 1998. pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167.
Johnson EM, Deckwerth TL Jr. 1993. Molecular mechanisms of developmental neuronal
death. Annu. Rev. Neurosci. 16:3146
Johnson EM, Rich KM, Yip HK. 1986. The role
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


of NGF in sensory neurons in vivo. Trends
Neurosci. 9:3337
Kaplan DR, Hempstead BL, Martin-Zanca
D, Chao MV, Parada LF. 1991a. The trk
proto-oncogene product: a signal transducing receptor for nerve growth factor. Science
252:55458
Kaplan DR, Martin-Zanca D, Parada LF. 1991b.
Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature 350:15860
Kaplan DR, Miller FD. 1997. Signal transduction by the neurotrophin receptors. Curr.
Opin. Cell. Biol. 9:21321
Karlsson M, Clary DO, Lefcort FB, Reichardt
LF, Karten HJ, Hallbook F. 1998. Nerve
growth factor receptor TrkA is expressed
by horizontal and amacrine cells during
chicken retinal development. J. Comp. Neurol. 400:40816
Kawaja MD, Gage FH. 1991. Reactive astrocytes are substrates for the growth of adult
CNS axons in the presence of elevated levels
of nerve growth factor. Neuron 7:101930
Kew JNC, Smith DW, Sofroniew MV. 1996.
Nerve growth factor withdrawal induces
the apoptotic death of developing septal
cholinergic neurons in vitro: protection by
cAMP analogue and high K+. Neuroscience
70:32939
Khasar SG, Lin YH, Martin A, Dadgar J,
McMahon T, et al. 1999. A novel nociceptor
signaling pathway revealed in protein kinase
C epsilon mutant mice. Neuron 24:25360
Khursigara G, Orlinick JR, Chao MV. 1999. Association of the p75 neurotrophin receptor
with TRAF6. J. Biol. Chem. 274:2597600
Klein R, Jing SQ, Nanduri V, ORourke E, Barbacid M. 1991. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell
65:18997
Klesse LJ, Parada LF. 1998. p21 ras and
phosphatidylinositol-3 kinase are required
for survival of wild-type and NF1 mutant sensory neurons. J. Neurosci. 8:1042028
Klippel A, Kavanaugh WM, Pot D, Williams
LT. 1997. A specific product of phos-
1267
phatidylinositol 3-kinase directly activates

the protein kinase Akt through its pleckstrin
homology domain. Mol. Cell. Biol. 17:338
44
Knipper M, Berzaghi MP, Blochl A, Breer
H, Thoenen H, Lindholm D. 1994. Positive
feedback between acetylcholine and the neurotrophins nerve growth factor and brainderived growth factor in the rat hippocampus.
Eur. J. Neurosci. 6:66871
Kobayashi M, Nagata S, Kita Y, Nakatsu N,
Ihara S, et al. 1997. Expression of a constitutively active phosphatidylinositol 3-kinase
induces process formation in rat PC12 cells.
Use of Cre/loxP recombination system. J.
Biol. Chem. 272:1608992
Koh S, Higgins GA. 1991. Differential regulation of the low-affinity nerve growth factor
receptor during postnatal development of the
rat brain. J. Comp. Neurol. 313:494508
Kolch W, Heidecker G, Kochs G, Hummel R,
Vahidi H, et al. 1993. Protein kinase C alpha
activates RAF-1 by direct phosphorylation.
Nature 364:24952
Kordower JH, Burke-Watson M, Roback JD,
Wainer BH. 1993. Stability of septohippocampal neurons following excitotoxic lesions of the rat hippocampus. Exp. Neurol.
117:116
Kordower JH, Winn SR, Liu Y, Mufson EJ,
Sladek JR, et al. 1994. The aged monkey
basal forebrain: rescue and sprouting of axotomized basal forebrain neurons after grafts
of encapsulated cells secreting human nerve
growth factor. Proc. Natl. Acad. Sci. USA
91:10898902
Korhonen JM, Said FA, Wong AJ, Kaplan
DR. 1999. Gab1 mediates neurite outgrowth,
DNA synthesis, and survival in PC12 cells.
J. Biol. Chem. 274:3730714
Korner M, Tarantino N, Pleskoff O, Lee LM,
Debre P. 1994. Activation of nuclear factor
kappa B in human neuroblastoma cell lines.
J. Neurochem. 62:171626
Kouhara H, Hadari YR, Spivak-Kroizman T,
Schilling J, Bar-Sagi D, et al. 1997. A lipidanchored Grb2-binding protein that links
P1: GDL
April 13, 2001

1268
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
FGF-receptor activation to the Ras/MAPK

signaling pathway. Cell 89:693702
Kremer NE, DArcangelo G, Thomas SM, DeMarco M, Brugge JS, Halegoua S. 1991. Signal transduction by nerve growth factor and
fibroblast growth factor in PC12 cells requires a sequence of src and ras actions. J.
Cell Biol. 115:80919
Krenz NR, Meakin SO, Krassioukov AV,
Weaver LC. 1999. Neutralizing intraspinal
nerve growth factor blocks autonomic dysreflexia caused by spinal cord injury. J. Neurosci. 19:7405
Kroemer G. 1997. The proto-oncogene Bcl-2
and its role in regulating apoptosis. Nat. Med.
3:61420
Kruttgen A, Moller J, Heymach JV, Shooter
EM. 1998. Neurotrophins induce release
of neurotrophins by the regulated secretory pathway. Proc. Natl. Acad. Sci. USA
95:961419
Kumar S, Pena L, de Vellis J. 1993. CNS glial
cells express neurotrophin receptors whose
levels are regulated by NGF. Brain Res. Mol.
Brain Res. 17:16368
Kuo WL, Chung KC, Rosner MR. 1997. Differentiation of central nervous system neuronal
cells by fibroblast-derived growth factor requires at least two signaling pathways: roles
for Ras and Src. Mol. Cell. Biol. 17:463343
Labouyrie E, Parrens M, de Mascarel A, Bloch
B, Merlio JP. 1997. Distribution of NGF receptors in normal and pathologic human lymphoid tissues. J. Neuroimmunol. 77:16173
Ladiwala U, Lachance C, Simoneau SJ, Bhakar
A, Barker PA, Antel JP. 1998. p75 neurotrophin receptor expression on adult human oligodendrocytes: signaling without cell
death in response to NGF. J. Neurosci.
18:1297304
Lai KO, Fu WY, Ip FCF, Ip NY. 1998. Cloning
and expression of a novel neurotrophin,
NT-7, from carp. Mol. Cell. Neurosci. 11:64
76
Lam HHD, Bhardwaj A, OConnell MT, Hanley DF, Traystman RJ, Sofroniew MV. 1998.
Nerve growth factor rapidly suppresses basal,
NMDA-evoked, and AMPA-evoked nitric

oxide synthase activity in rat hippocampus in
vivo. Proc. Natl. Acad. Sci. USA 95:10926
31
Lambiase A, Bracci-Laudiero L, Bonini S,
Bonini S, Starace G, et al. 1997. Human
CD4+ T cell clones produce and release
nerve growth factor and express high-affinity
nerve growth factor receptors. J. Allergy Clin.
Immunol. 100:40814
Landreth GE, Shooter EM. 1980. Nerve growth
factor receptors on PC12 cells: ligandinduced conversion from low- to highaffinity states. Proc. Natl. Acad. Sci. USA
77:475155
Lange-Carter CA, Johnson GL. 1994. Rasdependent growth factor regulation of MEK
kinase in PC12 cells. Science 265:145861
Large TH, Weskamp G, Helder JC, Radeke MJ,
Misko TP, et al. 1989. Structure and developmental expression of the nerve growth factor
receptor in the chicken central nervous system. Neuron 2:112334
Le Good JA, Ziegler WH, Parekh DB, Alessi
DR, Cohen P, Parker PJ. 1998. Protein kinase
C isotypes controlled by phosphoinositide
3-kinase through the protein kinase PDK1.
Science 281:204245
Lee J, Wang Z, Luoh SM, Wood WI, Scadden DT. 1994a. Cloning of FRK, a novel human intracellular SRC-like tyrosine kinaseencoding gene. Gene 138:24751
Lee KF, Bachman K, Landis S, Jaenisch R.
1994b. Dependence on p75 for innervation of some sympathetic targets. Science
263:144749
Lee KF, Davies AM, Jaenisch R. 1994c. p75deficient embryonic dorsal root sensory and
neonatal sympathetic neurons display a decreased sensitivity to NGF. Development
120:102733
Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH,
et al. 1992. Targeted mutation of the gene
encoding the low affinity NGF receptor p75
leads to deficits in the peripheral sensory nervous system. Cell 69:73749
Lee SB, Rhee SG. 1995. Significance of PIP2
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


hydrolysis and regulation of phospholipase C
isozymes. Curr. Opin. Cell Biol. 7:18389
Lehmann M, Fourneir A, Selles-Navarro I,
Dergham P, Sebok A, et al. 1999. Inactivation of rho signaling pathway promotes CNS
axon regeneration. J. Neurosci. 19:753747
Lemke G, Chao M. 1988. Axons regulate Schwann cell expression of the major
myelin and NGF receptor genes. Development 102:499504
Leon A, Buriani A, Dal Toso R, Fabris M, Romanello S, et al. 1994. Mast cells synthesize,
store, and release nerve growth factor. Proc.
LeSauteur L, Cheung NV, Lisbona R, Saragovi
HU. 1996. Small molecule nerve growth factor analogues image receptors in vivo. Nat.
Biotechnol. 14:112022
Levi-Montalcini R, Hamburger V. 1951. Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of chick embryo. J. Exp. Zool.
116:32161
Levi-Montalcini R, Hamburger V. 1953. A diffusible agent of mouse sarcoma, producing
hyperplasia of sympathetic ganglia and hyperneurotization of viscera in the chick embryo. J. Exp. Zool. 123:23387
Levi-Montalcini R, Skaper SD, Toso RD, Petrelli L, Leon A. 1996. Nerve growth factor:
from neurotrophin to neurokine. Trends Neurosci. 19:51420
Levi-Montalcini R, Toso RD, Valle FD, Skaper
SD, Leon A. 1995. Update of the NGF saga.
J. Neurol. Sci. 130:11927
Lewis TS, Shapiro PS, Ahn NG. 1998. Signal
transduction through MAP kinase cascades.
Adv. Cancer Res. 74:49139
Li Y, Holtzman DM, Kromer LF, Kaplan DR,
Chua-Couzens J, et al. 1995. Regulation of
TrkA and ChAT expression in developing rat
basal forebrain: evidence that both exogenous and endogenous NGF regulate differentiation of cholinergic neurons. J. Neurosci.
15:2888905
Liepinsh E, Ilag LL, Otting G, Ibanez CF. 1997.
NMR structure of the death domain of the p75
1269
neurotrophin receptor. EMBO J. 16:4999

5005
Lindholm D, Heumann R, Meyer M, Thoenen
H. 1987. Interleukin-1 regulates synthesis of
nerve growth factor in non-neuronal cells of
rat sciatic nerve. Nature 330:65859
Lindsay RM, Harmar AJ. 1989. Nerve growth
factor regulates expression of neuropeptide genes in adult sensory neurons. Nature
337:36264
Lindvall O, Kokaia Z, Bengzon J, Elmer E,
Kokaia M. 1994. Neurotrophins and brain insults. Trend. Neurosci. 17:49096
Liu YZ, Chrivia JC, Latchman DS. 1998. Nerve
growth factor upregulates the transcriptional
activity of CBP through activation of the
p42/p44(MAPK) cascade. J. Biol. Chem.
273:32400407
Liu ZG, Hsu H, Goeddel DV, Karin M. 1996.
Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell
death. Cell 87:56576
Liuzzo J, Petanceska S, Devi L. 1999. Neurotrophic factors regulate cathepsin S in macrophages and microglia: a role in the degradation of myelin basic protein and amyloid
beta peptide. Mol. Med. 5:33443
Liyanage M, Frith D, Livneh E, Stabel S. 1992.
Protein kinase C group B members PKCdelta, -epsilon, -zeta and PKC-L(eta). Comparison of properties of recombinant proteins
in vitro and in vivo. Biochem. J. 283:78187
Loeb DM, Maragos J, Martin-Zanca D, Chao
MV, Parada LF, Greene LA. 1991. The trk
proto-oncogene rescues NGF responsiveness
in mutant NGF-nonresponsive PC12 cell
lines. Cell 66:96166
Loeb DM, Stephens RM, Copeland T, Kaplan
DR, Greene LA. 1994. A Trk nerve growth
factor (NGF) receptor point mutation affecting interaction with phospholipase C-gamma
1 abolishes NGF-promoted peripherin induction but not neurite outgrowth. J. Biol. Chem.
269:890110
Longo FM, Holtzman DM, Grimes ML, Mobley WC. 1993. Nerve growth factor: actions
P1: GDL
April 13, 2001

1270
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
in the peripheral and central nervous systems.

In Neurotrophic Factors, ed. SE Loughlin,
JH Fallon. San Deigo, CA: Academic. 209
56
Longo FM, Mobley WC. 1996. Minimized
hormones grow in stature. Nat. Biotechnol.
14:1092
Lucidi-Phillipi CA, Clary DO, Reichardt LF,
Gage FH. 1996. TrkA activation is sufficient
to rescue axotomized cholinergic neurons.
Neuron 16:65363
Luo J, West JR, Pantazis NJ. 1997. Nerve
growth factor and basic fibroblast growth factor protect rat cerebellar granule cells in culture against ethanol-induced cell death. Alcohol Clin. Exp. Res. 21:110820
Luo Z, Diaz B, Marshall MS, Avruch J. 1997.
An intact Raf zinc finger is required for optimal binding to processed Ras and for rasdependent Raf activation in situ. Mol. Cell.
Biol. 17:4653
MacDonald JI, Gryz EA, Kubu CJ, Verdi JM,
Meakin SO. 2000. Direct binding of the signaling adapter protein Grb2 to the activation
loop tyrosines on the nerve growth factor receptor tyrosine kinase, TrkA. J. Biol. Chem.
275:1822533
MacPhee IJ, Barker PA. 1997. Brain-derived
neurotrophic factor binding to the p75 neurotrophin receptor reduces TrkA signaling
while increasing serine phosphorylation in
the TrkA intracellular domain. J. Biol. Chem.
272:2354751
Madison RD, Archibald SJ. 1994. Point sources
of Schwann cells result in growth into a nerve
entubulation repair site in the absence of axons: effects of freeze-thawing. Exp. Neurol.
128:26675
Mahadeo D, Kaplan L, Chao MV, Hempstead
BL. 1994. High affinity nerve growth factor
binding displays a faster rate of association
than p140trk binding. Implications for multisubunit polypeptide receptors. J. Biol. Chem.
269:688491
Maggirwar SB, Sarmiere PD, Dewhurst S,
Freeman RS. 1998. Nerve growth factordependent activation of NF-kappaB con-
tributes to survival of sympathetic neurons.

J. Neurosci. 18:1035665
Majdan M, Lachance C, Gloster A, Aloyz R,
Zeindler C, et al. 1997. Transgenic mice
expressing the intracellular domain of the
p75 neurotrophin receptor undergo neuronal
apoptosis. J. Neurosci. 17:698898
Malcangio M, Garrett NE, Tomlinson DR.
1997. Nerve growth factor treatment increases stimulus-evoked release of sensory
neuropeptides in the rat spinal cord. Eur. J.
Neurosci. 9:11014
Malinin NL, Boldin MP, Kovalenko AV, Wallach D. 1997. MAP3K-related kinase involved in NF-kappaB induction by TNF,
CD95 and IL-1. Nature 385:54044
Mallett S, Barclay AN. 1991. A new superfamily of cell surface proteins related to the
nerve growth factor receptor. Immunol. Today 12:22023
Marais R, Light Y, Mason C, Paterson H, Olson
MF, Marshall CJ. 1998. Requirement of RasGTP-Raf complexes for activation of Raf-1
by protein kinase C. Science 280:10912
Marshall CJ. 1994. MAP kinase kinase kinase,
MAP kinase kinase and MAP kinase. Curr.
Opin. Genet. Dev. 4:8289
Marshall JS, Gomi K, Blennerhassett MG, Bienenstock J. 1999. Nerve growth factor modifies the expression of inflammatory cytokines
by mast cells via a prostanoid-dependent
mechanism. J. Immunol. 162:427176
Martin-Zanca D, Hughes SH, Barbacid M.
1986a. A human oncogene formed by the
fusion of truncated tropomyosin and protein
tyrosine kinase sequences. Nature 319:743
48
Martin-Zanca D, Mitra G, Long LK, Barbacid
M. 1986b. Molecular characterization of the
human trk oncogene. Cold Spring Harb.
Symp. Quant. Biol. 51:98392
Martin-Zanca D, Oskam R, Mitra G, Copeland
T, Barbacid M. 1989. Molecular and
biochemical characterization of the human
trk proto-oncogene. Mol. Cell. Biol. 9:2433
Martinex-Serrano A, Bjorklund A. 1996. Protection of the neostriatum against excitotoxic
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


damage by neurotrophin-producing, genetically modified neural stem cells. J. Neurosci.
16:4604
Martnez-Murillo R, Fernandez AP, Bentura
ML, Rodrigo J. 1998. Subcellular localization of low-affinity nerve growth factor
receptor-immunoreactive protein in adult rat
purkinje cells following traumatic injury.
Exp. Brain Res. 119:4757
Matsuda M, Hashimoto Y, Muroya K,
Hasegawa H, Kurata T, et al. 1994. CRK
protein binds to two guanine nucleotidereleasing proteins for the Ras family and
modulates nerve growth factor-induced activation of Ras in PC12 cells. Mol. Cell. Biol.
14:5495500
Mattson M. 1996. Calcium and free radicals:
mediators of neurotrophic factor and excitatory transmitter-regulated developmental
plasticity and cell death. Perspect. Dev. Neurobiol. 3:7991
Mattson M, Marck R. 1996. Excitotoxicity and
excitoprotection in vitro. Adv. Neurol. 71:1
30
Mattson MP. 1997. Neuroprotective signal
transduction: relevance to stroke. Neurosci.
Biobehav. Rev. 21:193206
Mattson MP, Goodman Y, Luo H, Fu W, Furukawa K. 1997. Activation of NF-kappaB
protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for
induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration. J. Neurosci. Res. 49:68197
Mattson MP, Lovell MA, Furukawa K, Markesbery WR. 1995. Neurotrophic factors attenuate glutamate-induced accumulation of
peroxides, elevation of intracellular Ca2+
concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J. Neurochem. 65:1740
51
McAllister AK. 1999. Neurotrophins and
synaptic plasticity. Annu. Rev. Neurosci.
22:295318
McCormick F. 1994. Activators and effectors
1271
of ras p21 proteins. Curr. Opin. Genet. Dev.

4:7176
McDonald NQ, Lapatto R, Murray-Rust J, Gunning J, Wlodawer A, Blundell TL. 1991. New
protein fold revealed by a 2.3-A resolution
crystal structure of nerve growth factor. Nature 354:41114
McMahon SB, Bennete DLH, Priestley JV,
Shelton DL. 1995. The biological effects of
endogenous nerve growth factor on adult sensory neurons revealed by a trkA-IgG fusion
molecule. Nat. Med. 1:774
McMartin DN, OConnor JA. 1979. Effect of age on axoplasmic transport of
cholinesterase in rat sciatic nerves. Mech.
Ageing Dev. 10:24148
Meakin SO, MacDonald JI, Gryz EA, Kubu CJ,
Verdi JM. 1999. The signaling adapter FRS2 competes with Shc for binding to the nerve
growth factor receptor TrkA. A model for discriminating proliferation and differentiation.
J. Biol. Chem. 274:986170
Meakin SO, Shooter EM. 1992. The nerve
growth factor family of receptors. Trends
Neurosci. 15:32331
Meakin SO, Suter U, Drinkwater CC, Welcher
AA, Shooter EM. 1992. The rat trk protooncogene product exhibits properties characteristic of the slow nerve growth factor receptor. Proc. Natl. Acad. Sci. USA 89:2374
78
Meller N, Liu YC, Collins TL, BonnefoyBerard N, Baier G, et al. 1996. Direct interaction between protein kinase C theta (PKC
theta) and 14-3-3 tau in T cells: 14-3-3 overexpression results in inhibition of PKC theta
translocation and function. Mol. Cell. Biol.
16:578291
Mendell LM. 1996. Neurotrophins and sensory neurons: role in development, maintenance and injury. A thematic summary. Philos. Trans. R. Soc. London Ser. B 351:46367
Mendell LM, Albers KM, Davis BM. 1999.
Neurotrophins, nociceptors, and pain. Microsc. Res. Technol. 45:25261
Menniti FS, Oliver KG, Putney JW Jr, Shears
SB. 1993. Inositol phosphates and cell
P1: GDL
April 13, 2001

1272
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
signaling: new views of InsP5 and InsP6.

Trends Biochem. Sci. 18:5356
Merry DE, Korsmeyer SJ. 1997. cl-2 gene family in the nervous system. Annu. Rev. Neurosci. 20:24567
Micera A, Vigneti E, Aloe L. 1998. Changes
of NGF presence in nonneuronal cells
in response to experimental allergic encephalomyelitis in lewis rats. Exp. Neurol.
154:4146
Michael GJ, Kaya E, Averill S, Rattry M, Clay
DO, Priestley JV. 1997. TrkA immunoreactive neurones in the rat spinal cord. J. Comp.
Neurol. 385:44155
Middlemas DS, Meisenhelder J, Hunter T.
1994. Identification of TrkB autophosphorylation sites and evidence that phospholipase
C-gamma 1 is a substrate of the TrkB receptor. J. Biol. Chem. 269:545866
Miller FD, Mathew TC, Toma JG. 1991. Regulation of nerve growth factor receptor gene
expression by nerve growth factor in the developing peripheral nervous system. J. Cell
Biol. 112:30312
Miller FD, Speelman A, Mathew TC, Fabian J,
Chang E, et al. 1994. Nerve growth factor derived from terminals selectively increases the
ratio of p75 to trkA NGF receptors on mature
sympathetic neurons. Dev. Biol. 161:206
17
Miranti CK, Ginty DD, Huang G, Chatila
T, Greenberg ME. 1995. Calcium activates
serum response factor-dependent transcription by a Ras- and Elk-1-independent mechanism that involves a Ca2+/calmodulindependent kinase. Mol. Cell. Biol. 15:3672
84
Mirsky R, Jessen KR. 1999. The neurobiology
of Schwann cells. Brain Pathol. 9:293311
Mizuma H, Takagi K, Miyake K, Takagi N,
Ishida K, et al. 1999. Microsphere embolisminduced elevation of nerve growth factor level
and appearance of nerve growth factor immunoreativity in activated T-lymphocytes in
the rat brain. J. Neurosci. Res. 55:74961
Mobley WC, Rutkowski JL, Tennekoon GI,
Buchanan K, Johnston M. 1985. Choline
acetyltransferase activity in striatum of

neonatal rats increased by nerve growth factor. Science 229:28487
Moller DE, Xia CH, Tang W, Zhu AX,
Jakubowski M. 1994. Human rsk isoforms: cloning and characterization of tissuespecific expression. Am. J. Physiol. 266:
C35159
Morrison ME, Mason CA. 1998. Granule neuron regulation of purkinje cell development:
striking a balance between neurotrophin and
glutamate signaling. J. Neurosci. 18:3563
73
Mueller CG, Nordheim A. 1991. A protein domain conserved between yeast MCM1 and
human SRF directs ternary complex formation. EMBO J. 10:421929
Mufson EJ, Lavine N, Jaffar S, Kordower JH,
Quirion R, Saragovi HU. 1997. Reduction in
p140-TrkA receptor protein within the nucleus basalis and cortex in Alzheimers disease. Exp. Neurol. 146:91103
Muragaki Y, Chou TT, Kaplan DR, Trojanowski
JQ, Lee VM. 1997. Nerve growth factor induces apoptosis in human medulloblastoma
cell lines that express TrkA receptors. J. Neurosci. 17:53042
Muroya K, Hattori S, Nakamura S. 1992. Nerve
growth factor induces rapid accumulation
of the GTP-bound form of p21ras in rat
pheochromocytoma PC12 cells. Oncogene
7:27781
Nakajima T, Fukamizu A, Takahashi J, Gage
FH, Fisher T, et al. 1996. The signaldependent coactivator CBP is a nuclear target
for pp90RSK. Cell 86:46574
Neumann S, Woolf CJ. 1999. Regeneration of
dorsal column fibers into and beyond the lesion site following adult spinal cord injury.
Neuron 23:8391
Nishizuka Y. 1988. The molecular heterogeneity of protein kinase C and its implications
for cellular regulation. Nature 334:66165
Nishizuka Y. 1992. Intracellular signaling by
hydrolysis of phospholipids and activation of
protein kinase C. Science 258:60714
Noda M, Ko M, Ogura A, Liu DG, Amano
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


T, et al. 1985. Sarcoma viruses carrying ras
oncogenes induce differentiation- associated
properties in a neuronal cell line. Nature
318:7375
Obermeier A, Bradshaw RA, Seedorf K,
Choidas A, Schlessinger J, Ullrich A. 1994.
Neuronal differentiation signals are controlled by nerve growth factor receptor/Trk
binding sites for SHC and PLC gamma.
EMBO J. 13:158590
Oberwetter JM, Conrad KE, GutierrezHartmann A. 1993. The Ras and protein
kinase C signaling pathways are functionally
antagonistic in GH4 neuroendocrine cells.
Mol. Endocrinol. 7:91523
OBrien TS, Svendsen CN, Isacson O,
Sofroniew MV. 1990. Loss of True blue labelling from the medial septum following
transection of the fimbria-fornix: evidence
for the death of cholinergic and noncholinergic neurons. Brain Res. 508:24956
Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, et al. 2000. FRS2 proteins recruit
intracellular signaling pathways by binding
to diverse targets on fibroblast growth factor
and nerve growth factor receptors. Mol. Cell.
Biol. 20:97989
Ono Y, Fujii T, Ogita K, Kikkawa U, Igarashi
K, Nishizuka Y. 1988. The structure, expression, and properties of additional members
of the protein kinase C family. J. Biol. Chem.
263:692732
Osada S, Mizuno K, Saido TC, Akita Y,
Suzuki K, et al. 1990. A phorbol ester receptor/protein kinase, nPKC eta, a new member
of the protein kinase C family predominantly
expressed in lung and skin. J. Biol. Chem.
265:2243440
Osada S, Mizuno K, Saido TC, Suzuki K,
Kuroki T, Ohno S. 1992. A new member
of the protein kinase C family, nPKC theta,
predominantly expressed in skeletal muscle.
Oshima M, Sithanandam G, Rapp UR, Guroff
G. 1991. The phosphorylation and activation
of B-raf in PC12 cells stimulated by nerve
growth factor. J. Biol. Chem. 266:2375360
1273
Otten U, Scully JL, Ehrhard PB, Gadient RA.

1994. Neurotrophins: signals between the
nervous and immune systems. Prog. Brain
Res. 103:293305
Pang L, Sawada T, Decker SJ, Saltiel AR.
1995. Inhibition of MAP kinase kinase
blocks the differentiation of PC-12 cells induced by nerve growth factor. J. Biol. Chem.
270:1358588
Pascual M, Rocamora N, Acsady L, Freund
TF, Soriano E. 1998. Expression of nerve
growth factor and neurotrophin-3 mRNAs
in hippocampal interneurons: morphological characterization, levels of expression, and
colocalization of nerve growth factor and
neurotrophin-3. J. Comp. Neurol. 395:7390
Patel TD, Jackman A, Rice FL, Kucera J, Snider
WD. 2000. Development of sensory neurons
in the absence of NGF/TrkA signaling in vivo
[see comments]. Neuron 25:34557
Payne DM, Rossomando AJ, Martino P, Erickson AK, Her JH, et al. 1991. Identification of the regulatory phosphorylation
sites in pp42/mitogen-activated protein kinase (MAP kinase). EMBO J. 10:88592
Pearson RCA, Sofroniew MV, Cuello AC, Powell TPS, Eckenstein F, et al. 1983. Persistance of cholinergic neurons in the basal nucleus in a brain with senile dementia of the
Alzheimers type demonstrated by immunohistochemical staining for choline acetyltransferase. Brain Res. 289:37579
Pechan PA, Chowdhury K, Gerdes W, Seifert
W. 1993. Glutamate induces the growth factors NGF and bFGF, the receptors FGF-R1
and c-fos mRNA expression in rat astrocyte
culture. Neurosci. Lett. 16:11114
Pechan PA, Chowdhury K, Seifert W. 1992.
Free radicals induce gene expression of NGF
and bFGF in rat astrocyte culture. NeuroReport 3:46972
Peterson DA, Dickinson-Anson HA, Leppert
JT, Lee KF, Gage FH. 1999. Central neuronal
loss and behavioral impairment in mice lacking neurotrophin receptor p75. J. Comp. Neurol. 404:120
Petty B, Cornblath DR, Adornato BT, Chaudry
P1: GDL
April 13, 2001

1274
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
V, Flexner C, et al. 1994. The effect of sytemically administered recombinant human nerve
growth factor in healthy human subjects.
Ann. Neurol. 36:24446
Pitts AF, Miller MW. 2000. Expression of nerve
growth factor, brain-derived neurotrophic
factor, and neurotrophin-3 in the somatosensory cortex of the mature rat: coexpression
with high-affinity neurotrophin receptors. J.
Comp. Neurol. 418:24154
Pizzorusso T, Berardi N, Rossi FM, Viegi A,
Venstrom K, et al. 1999. TrkA activation in
the rat visual cortex by antirat trkA IgG prevents the effect of monocular deprivation.
Eur J. Neurosci. 11:20412
Prakash N, Cohen-Cory S, Frostig RD. 1996.
Rapid and opposite effects of BDNF and
NGF on the functional organization of the
adult cortex in vivo. Nature 381:7026
Qian X, Riccio A, Zhang Y, Ginty DD. 1998.
Identification and characterization of novel
substrates of Trk receptors in developing neurons. Neuron 21:101729
Qui MS, Green SH. 1992. PC12 cell neuronal
differentiation is associated with prolonged
p21ras activity and consequent prolonged
ERK activity. Neuron 9:70517
Rabin SJ, Cleghon V, Kaplan DR. 1993.
SNT, a differentiation-specific target of neurotrophic factor-induced tyrosine kinase activity in neurons and PC12 cells. Mol. Cell.
Biol. 13:220313
Rabizadeh S, Oh J, Zhong LT, Yang J, Bitler
CM, et al. 1993. Induction of apoptosis by the
low-affinity NGF receptor. Science 261:345
48
Ramer MS, Priestley JV, McMahon SB. 2000.
Functional regeneration of sensory axons
into the adult spinal cord. Nature 403:31216
Ramirez S, Ait-Si-Ali S, Robin P, Trouche D,
Harel-Bellan A. 1997. The CREB-binding
protein (CBP) cooperates with the serum
response factor for transactivation of the
c-fos serum response element. J. Biol. Chem.
272:3101621
Ribon V, Saltiel AR. 1996. Nerve growth factor stimulates the tyrosine phosphorylation
of endogenous Crk-II and augments its association with p130Cas in PC-12 cells. J. Biol.
Chem. 271:737580
Riccio A, Ahn S, Davenport CM, Blendy JA,
Ginty DD. 1999. Mediation by a CREB family transcription factor of NGF-dependent
survival of sympathetic neurons. Science
286:235861
Riccio A, Pierchala BA, Ciarello CL, Ginty
DD. 1997. An NGF-TrkA-mediated retrograde signal to transcription factor CREB
in sympathetic neurons. Science 277:1097
100
Rice FL, Albers KM, Davis BM, Silos-Santiago
I, Wilkinson GA, et al. 1998. Differential dependency of unmyelinated and A delta epidermal and upper dermal innervation on neurotrophins, trk receptors, and p75LNGFR.
Dev. Biol. 198:5781
Rich KM, Alexander TD, Pryor JC, Hollowell
JP. 1989. Nerve growth factor enhances regeneration through silicone chambers. Exp.
Neurol. 105:16270
Richardson PM, Issa VM. 1984. Peripheral injury enhances entral regeneration of primary
sensory neurones. Nature 309:79193
Robinson RC, Radziejewski C, Spraggon G,
Greenwald J, Kostura MR, et al. 1999.
The structures of the neurotrophin 4 homodimer and the brain-drived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site. Protein Sci. 8:258997
Robinson RC, Radziejewski C, Stuart DI, Jones
EY. 1995. Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer.
Biochemistry 34:413946
Ross AH, Daou MC, McKinnon CA, Condon
PJ, Lachyankar MB, et al. 1996. The neurotrophin receptor, gp75, forms a complex
with the receptor tyrosine kinase TrkA. J.
Cell Biol. 132:94553
Ross GM, Shamovsky IL, Lawrance G, Solc M,
Dostaler SM, et al. 1998. Reciprocal modulation of TrkA and p75NTR affinity states is
mediated by direct receptor interactions. Eur.
Rothe M, Sarma V, Dixit VM, Goeddel DV.
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


1995. TRAF2-mediated activation of NFkappa B by TNF receptor 2 and CD40. Science 269:142427
Rothstein JD, Dykes-Hoberg M, Pardo CA,
Bristol LA, Jin L, et al. 1996. Knockout of
glutamate transporters reveals a major role
for astroglial transport in excitotoxicity and
clearance of glutamate. Neuron 16:67586
Rozakis-Adcock M, McGlade J, Mbamalu G,
Pelicci G, Daly R, et al. 1992. Association
of the Shc and Grb2/Sem5 SH2-containing
proteins is implicated in activation of the
Ras pathway by tyrosine kinases. Nature
360:68992
Ruit KG, Osborne PA, Schmidt RE, Johnson
EM Jr, Snider WD. 1990. Nerve growth factor regulates sympathetic ganglion cell morphology and survival in the adult mouse. Neuroscience 10:241219
Ryden M, Ibanez CF. 1997. A second determinant of binding to the p75 neurotrophin
receptor revealed by alanine-scanning mutagenesis of a conserved loop in nerve growth
factor. J. Biol. Chem. 272:3308591
Saper CB, Wainer BH, German DC. 1987. Axonal and transneuronal transport in the transmission of neurological disease: potential
role in systems degeneration. Neuroscience
23:38997
Schechter AL, Bothwell MA. 1981. Nerve
growth factor receptors on PC12 cells: evidence for two receptor classes with differing
cytoskeletal association. Cell 24:86774
Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M. 1999. NFkappaB is activated and promotes cell death
in focal cerebral ischemia. Nat. Med. 5:554
59
Schonwasser DC, Marais RM, Marshall CJ,
Parker PJ. 1998. Activation of the mitogenactivated protein kinase/extracellular signalregulated kinase pathway by conventional,
novel, and atypical protein kinase C isotypes.
Schouten GJ, Vertegaal AC, Whiteside ST, Israel A, Toebes M, et al. 1997. IkappaB alpha is a target for the mitogen-activated 90
1275
kDa ribosomal S6 kinase. EMBO J. 16:3133

44
Schumacher JM, Short MP, Hyman BT, Breakfield XO, Isacson O. 1991. Intracerebral implantation of nerve growth factor-producing
fibroblasts protects striatum against neurotoxic levels of excitatory amino acids. Neuroscience 43:56770
Schwaninger M, Sallmann S, Petersen N,
Schneider A, Prinz S, et al. 1999. Bradykinin
induces interleukin-6 expression in astrocytes through activation of nuclear factorkappaB. J. Neurochem. 73:146166
Scott SA, Mufson EJ, Weingartner JA, Skau
KA, Crutcher KA. 1995. Nerve growth factor in Alzheimers disease: increased levels
throughout the brain coupled with declines
in nucleus basalis. J. Neurosci. 15:6213
21
Seibenhener ML, Roehm J, White WO, Neidigh
KB, Vandenplas ML, Wooten MW. 1999.
Identification of Src as a novel atypical protein kinase C-interacting protein. Mol. Cell.
Biol. Res. Commun. 2:2831
Semkova I, Krieglstein J. 1999. Cilliary neurotrophic factor enhances the expression of
NGF and p75 low-affinity NGF receptor in
astrocytes. Brain Res. 838:18492
Sheng M, Greenberg ME. 1990. The regulation
and function of c-fos and other immediate
early genes in the nervous system. Neuron
4:47785
Shigeno T, Mima T, Takakura K, Graham DI,
Kato G, et al. 1991. Amelioration of delayed neuronal death in the hippocampus by
nerve growth factor. J. Neurosci. 11:2914
19
Shu XQ, Mendell LM. 1999. Neurotrophins
and hyperalgesia. Proc. Natl. Acad. Sci. USA
96:769396
Siliprandi R, Canella R, Carmignoto G.
1993. Nerve growth factor promotes functional recovery of retinal ganglion cells after ischemia. Invest. Ophthalmol. Vis. Sci.
34:323245
Simone M, De Santis S, Vigneti E, Papa G,
Amadori S, Aloe L. 1999. Nerve growth
P1: GDL
April 13, 2001

1276
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
factor: a survey of activity on immune and

hematopoietic cells. Hematol. Oncol. 17:1
10
Singer CA, Figueroa-Masot XA, Batchelor RH,
Dorsa DM. 1999. The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary
cortical neurons. J. Neurosci. 19:2455
Singh M, Setalo GJ, Guan X, Warren M, ToranAllerand CD. 1999. Estrogen-induced activation of mitogen-activated protein kinase in
cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways.
Smeyne RJ, Klein R, Schnapp A, Long LK,
Bryant S, et al. 1994. Severe sensory and
sympathetic neuropathies in mice carrying a
disrupted Trk/NGF receptor gene [see comments]. Nature 368:24649
Smith CA, Farrah T, Goodwin RG. 1994. The
TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and
death. Cell 76:95962
Snider WD. 1994. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us.
Cell 77:62738
Sofroniew MV. 1999. Neuronal responses to axotomy. In CNS Regeneration: Basic Science
and Clinical Advances, ed. M Tuszynski, J
Kordower, pp. 326. San Diego, CA: Academic
Sofroniew MV, Cooper JD, Svendsen CN,
Crossman P, Ip NY, et al. 1993. Atrophy but
not death of adult septal cholinergic neurons
after ablation of target capacity to produce
mRNAs for NGF, BDNF and NT-3. J. Neurosci. 13:526376
Sofroniew MV, Galletly NP, Isacson O, Svendsen CN. 1990. Survival of adult basal forebrain cholinergic neurons after loss of target
neurons. Science 247:33842
Sofroniew MV, Mobley WC. 1993. On the possibility of positive feedback in trophic interactions between afferent and target neurons.
Semin. Neurosci. 5:30912
Sofroniew MV, Pearson RCA, Eckenstein F,
Cuello AC, Powell TPS. 1983. Retrograde

changes in the basal forebrain of the rat following cortical damage. Brain Res. 289:370
74
Song HY, Dunbar JD, Donner DB. 1994. Aggregation of the intracellular domain of the
type 1 tumor necrosis factor receptor defined
by the two-hybrid system. J. Biol. Chem.
269:2249295
Sozeri O, Vollmer K, Liyanage M, Frith D, Kour
G, et al. 1992. Activation of the c-Raf protein
kinase by protein kinase C phosphorylation.
Oncogene 7:225962
Steller H. 1995. Mechanisms and genes of cellular suicide. Science 267:144549
Stephens L, Anderson K, Stokoe D, ErdjumentBromage H, Painter GF, et al. 1998. Protein
kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279:710
14
Stephens RM, Loeb DM, Copeland TD, Pawson T, Greene LA, Kaplan DR. 1994. Trk
receptors use redundant signal transduction
pathways involving SHC and PLC-gamma 1
to mediate NGF responses. Neuron 12:691
705
Stokoe D, Stephens LR, Copeland T, Gaffney
PR, Reese CB, et al. 1997. Dual role
of phosphatidylinositol-3,4,5-trisphosphate
in the activation of protein kinase B. Science
277:56770
Strauss S, Otten U, Joggerst B, Pluss K, Volk B.
1968. Increased levels of nerve growth factor
(NGF) protein and mRNA and reactive gliosis following kainic acid injection into the rat
striatum. Neurosci. Lett. 168:19396
Strijbos P, Rothwell N. 1995. Interleukin-1 beta
attenuates excitatory amino acid-induced
neurodegeneration in vitro: involvement of
nerve growth factor. J. Neurosci. 15:3468
Sturgill TW, Ray LB, Erikson E, Maller
JL. 1988. Insulin-stimulated MAP-2 kinase
phosphorylates and activates ribosomal protein S6 kinase II. Nature 334:71518
Susaki Y, Shimizu S, Katakura K, Watanabe
N, Kawamoto K, et al. 1996. Functional
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


properties of murine macrophages promoted
by nerve growth factor. Blood 88:463037
Susaki Y, Tanaka A, Honda E, Matsuda H. 1998.
Nerve growth factor modulates Fc gamma
receptor expression on murine macrophage
J774A.1 cells. J. Vet. Med. Sci. 60:8791
Sutter A, Riopelle RJ, Harris-Warrick RM,
Shooter EM. 1979. Nerve growth factor
receptors. Characterization of two distinct
classes of binding sites on chick embryo sensory ganglia cells. J. Biol. Chem. 254:5972
82
Svendsen CN, Kew JNC, Staley K, Sofroniew
MV. 1994. Death of developing septal cholinergic neurons following NGF withdrawal in
vitro: protection by protein synthesis inhibition. J. Neurosci. 14:7587
Taiwo YO, Levine JD, Burch R, Woo JE, Mobley WC. 1991. Hyperalgesia induced in the
rat by the amino-terminal octapeptide of
nerve growth factor. Proc. Natl. Acad. Sci.
USA 88:514448
Taniuchi M, Clark HB, Johnson EM Jr. 1986.
Induction of nerve growth factor receptor
in Schwann cells after axotomy. Proc. Natl.
Acad. Sci. USA 83:409498
Taniuchi M, Clark HB, Schweitzer JB, Johnson EM. 1988. Expression of nerve growth
factor receptors by Schwann cells of axotomized peripheral nerves: ultrastructural location, suppression by axonal contact, and
binding properties. J. Neurosci. 8:66481
Tartaglia LA, Ayres TM, Wong GH, Goeddel
DV. 1993. A novel domain within the 55 kd
TNF receptor signals cell death. Cell 74:845
53
Teng KK, Lander H, Fajardo JE, Hanafusa H,
Hempstead BL, Birge RB. 1995. v-Crk modulation of growth factor-induced PC12 cell
differentiation involves the Src homology 2
domain of v-Crk and sustained activation
of the Ras/mitogen-activated protein kinase
pathway. J. Biol. Chem. 270:2067785
Thomas SM, Brugge JS. 1997. Cellular functions regulated by Src family kinases. Annu.
Rev. Cell Dev. Biol. 13:513609
Thomas SM, Hayes M, DArcangelo G, Arm-
1277
strong RC, Meyer BE, et al. 1991. Induction

of neurite outgrowth by v-src mimics critical aspects of nerve growth factor-induced
differentiation. Mol. Cell. Biol. 11:4739
50
Thuveson M, Albrecht D, Zurcher G, Andres
AC, Ziemiecki A. 1995. iyk, a novel intracellular protein tyrosine kinase differentially
expressed in the mouse mammary gland and
intestine. Biochem. Biophys. Res. Commun.
209:58289
Toran-Allerand CD, Miranda RC, Bentham
WD, Sohrabji F, Brown TJ, et al. 1992. Estrogen receptors colocalize with low-affinity
nerve growth factor receptors in cholinergic
neurons of the basal forebrain. Proc. Natl.
Torcia M, Bracci-Laudiero L, Lucibello M,
Nencioni L, Labardi D, et al. 1996. Nerve
growth factor is an autocrine survival factor
for memory B lymphocytes. Cell 85:34556
Torres M, Bogenmann E. 1996. Nerve growth
factor induces a multimeric TrkA receptor complex in neuronal cells that includes
Crk, SHC and PLC-gamma 1 but excludes
P130CAS. Oncogene 12:7786
Traverse S, Cohen P. 1994. Identification of a latent MAP kinase kinase kinase in PC12 cells
as B-raf. FEBS Lett. 350:1318
Traverse S, Gomez N, Paterson H, Marshall
C, Cohen P. 1992. Sustained activation of
the mitogen-activated protein (MAP) kinase
cascade may be required for differentiation
of PC12 cells. Comparison of the effects of
nerve growth factor and epidermal growth
factor. Biochem. J. 288:35155
Treisman R. 1992. The serum response element.
Trends Biochem. Sci. 17:42326
Trim N, Morgan S, Evans M, Issa R, Fine D,
et al. 2000. Hepatic stellate cells express
the low affinity nerve growth factor receptor p75 and undergo apoptosis in response
to nerve growth factor stimulation. Am. J.
Pathol. 156:123543
Tsui-Pierchala BA, Ginty DD. 1999. Characterization of an NGF-P-TrkA retrogradesignaling complex and age-dependent
P1: GDL
April 13, 2001

1278
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
regulation of TrkA phosphorylation in sympathetic neurons. Neuroscience 19:820718

Tuszynski MH, Armstrong DM, Gage FH.
1990. Basal forebrain cell loss following fimbria/fornix transection. Brain Res. 508:241
48
Tuszynski MH, Gage FH. 1995a. Bridging
grafts and transient nerve growth factor infusions promote long-term central nervous system neuronal rescue and partial functional recovery. Proc. Natl. Acad. Sci. USA 92:4621
25
Tuszynski MH, Gage FH. 1995b. Maintaining the neuronal phenotype after injury in
the adult CNS. Neurotrophic factors, axonal
growth substrates, and gene therapy. Mol.
Neurobiol. 10:15167
Tuttle R, OLeary DDM. 1998. Neurotrophins
rapidly modulate growth cone response to the
axon guidance molecule, collapsin-1. Mol.
Cell. Neurosci. 11:18
Twiss JL, Shooter EM. 1995. Nerve growth factor promotes neurite regeneration in PC12
cells by translational control. J. Neurochem.
64:55057
Ueffing M, Lovric J, Philipp A, Mischak H,
Kolch W. 1997. Protein kinase C-epsilon associates with the Raf-1 kinase and induces
the production of growth factors that stimulate Raf-1 activity. Oncogene 15:292127
Ure DR, Campenot RB. 1997. Retrograde transport and steady-state distribution of 125Inerve growth factor in rat sympathetic neurons in compartmented cultures. J. Neurosci.
17:128290
Urfer R, Tsoulfas P, Soppet D, Escandon E,
Parada LF, Presta LG. 1994. The binding epitopes of neurotrophin-3 to its receptors trkC
and gp75 and the design of a multifunctional
human neurotrophin. EMBO J. 13:5896
909
Vaillancourt RR, Gardner AM, Johnson GL.
1994. B-Raf-dependent regulation of the
MEK-1/mitogen-activated protein kinase
pathway in PC12 cells and regulation by
cyclic AMP. Mol. Cell. Biol. 14:652230
Vaillant AR, Mazzoni I, Tudan C, Boudreau
M, Kaplan DR, Miller FD. 1999. Depolarization and neurotrophins converge on the
phosphatidylinositol 3-kinase-Akt pathway
to synergistically regulate neuronal survival.
J. Cell Biol. 146:95566
Van Aelst L, Barr M, Marcus S, Polverino
A, Wigler M. 1993. Complex formation between RAS and RAF and other protein kinases. Proc. Natl. Acad. Sci. USA 90:6213
17
Van Antwerp DJ, Martin SJ, Kafri T, Green DR,
Verma IM. 1996. Suppression of TNF-alphainduced apoptosis by NF-kappaB. Science
274:78789
van der Hoeven PCJ, van der Wal JCM, Ruurs P, van Dijk MCM, van Blitterswijk WJ.
2000. 14-3-3 isotypes facilitate coupling of
protein kinase C-zeta to Raf-1: negative regulation by 14-3-3 phosphorylation. Biochem.
J. 345:297306
van Dijk MC, Hilkmann H, van Blitterswijk
WJ. 1997. Platelet-derived growth factor
activation of mitogen-activated protein kinase depends on the sequential activation of
phosphatidylcholine-specific phospholipase
C, protein kinase C-zeta and Raf-1. Biochem.
J. 325:3037
Venero JL, Knusel B, Beck KD, Hefti F. 1994.
Expression of neurotrophin and trk receptor
genes in adult rats with fimbria transections:
effect of intraventricular nerve growth factor
and brain-derived neurotrophic factor administration. Neuroscience 59:797815
Verdi JM, Anderson DJ. 1994. Neurotrophins
regulate sequential changes in neurotrophin
receptor expression by sympathetic neuroblasts. Neuron 13:135972
Verge VM, Gratto KA, Karchewski LA,
Richardson PM. 1996. Neurotrophins and
nerve injury in the adult. Philos. Trans. R.
Soc. London Ser. B 351:42330
Verge VM, Merlio JP, Grondin J, Ernfors P,
Persson H, et al. 1992. Colocalization of NGF
binding sites, trk mRNA, and low-affinity
NGF receptor mRNA in primary sensory
neurons: responses to injury and infusion of
NGF. J. Neurosci. 12:401122
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


Verge VMK, Richardson PM, Benoit R, Riopelle RJ. 1989. Histochemical characterization of sensory neurons with high-affinity
receptors for nerve growth factor. J. Neurocytol. 18:58391
Verge VM, Richardson PM, Wiesenfeld-Hallin
Z, Hokfelt T. 1995. Differential influence of
nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons. J. Neurosci.
15:208196
Vetter ML, Martin-Zanca D, Parada LF, Bishop
JM, Kaplan DR. 1991. Nerve growth factor
rapidly stimulates tyrosine phosphorylation
of phospholipase C-gamma 1 by a kinase activity associated with the product of the trk
protooncogene. Proc. Natl. Acad. Sci. USA
88:565054
von Bussmann KA, Sofroniew MV. 1999. Reexpression of p75NTR by adult motor neurons after axotomy is triggered by retrograde
transport of a positive signal from regenerating peripheral nerve. Neuroscience 91:273
81
Wada K, Okada N, Yamamura Y, Koizumi S.
1996. Nerve growth factor induces resistance
of PC12 cells to nitric oxide cytotoxicity.
Neurochem. Int. 29:46167
Wang CY, Mayo MW, Baldwin AS Jr. 1996.
TNF- and cancer therapy-induced apoptosis:
potentiation by inhibition of NF-kappaB. Science 274:78487
Wang H, Tessier-Lavigne M. 1999. En passant neurotrophic action of an intermediate
axonal target in the developing mammalian
CNS. Nature 401:76569
Watanabe-Fukunaga R, Brannan CI, Copeland
NG, Jenkins NA, Nagata S. 1992. Lymphoproliferation disorder in mice explained by
defects in Fas antigen that mediates apoptosis. Nature 356:31417
Watson FL, Heerssen HM, Moheban DB,
Lin MZ, Sauvageot CM, et al. 1999.
Rapid nuclear responses to target-derived
neurotrophins require retrograde transport
of ligand-receptor complex. J. Neurosci.
9:7889900
1279
Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W. 1996.

Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 384:17376
Welch H, Maridonneau-Parini I. 1997. Lyn and
Fgr are activated in distinct membrane fractions of human granulocytic cells. Oncogene
15:202129
Whitehouse PJ, Price DL, Struble RG,
Clark AW, Coyle JT, DeLong MR. 1982.
Alzheimers disease and senile dementia:
loss of neurons in the basal forebrain. Science 215:123739
Wiesmann C, Ultsch MH, Bass SH, de Vos AM.
1999. Crystal structure of nerve growth factor
in complex with the ligand-binding domain
of the TrkA receptor. Nature 401:18488
Williams LR, Varon S, Peterson GM, Wictorin K, Fischer W, et al. 1986. Continuous infusion of nerve growth factor prevents
basal forebrain neuronal death after fimbria
fornix transection. Proc. Natl. Acad. Sci. USA
83:923135
Wills Z, Marr L, Zinn K, Goodman CS, Van
Vactor D. 1999. Profilin and the Abl tyrosine
kinase are required for motor axon outgrowth
in the Drosophila embryo. Neuron 22:29199
Wilson JX. 1997. Antioxidant defense of the
brain: a role for astrocytes. Can. J. Physiol.
Pharmacol. 75:114963
Winkler J, Ramirez GA, Thal LJ, Waite JJ.
2000. Nerve growth factor (NGF) augments cortical and hippocampal cholinergic
functioning afer p75NGF receptor-mediated
deafferentation but impairs inhibitory avoidance and induces fear-related behaviors. J.
Neurosci. 20:83444
Wolf DE, McKinnon CA, Daou MC, Stephens
RM, Kaplan DR, Ross AH. 1995. Interaction with TrkA immobilizes gp75 in the high
affinity nerve growth factor receptor complex. J. Biol. Chem. 270:213338
Wood JN. 1995. Regulation of NF-kappa B activity in rat dorsal root ganglia and PC12 cells
by tumour necrosis factor and nerve growth
factor. Neurosci Lett. 192:4144
P1: GDL
April 13, 2001

1280
18:17
Annual Reviews
SOFRONIEW
HOWE
AR121-40
MOBLEY
Wood KW, Sarnecki C, Roberts TM, Blenis J.

1992. ras mediates nerve growth factor receptor modulation of three signal-transducing
protein kinases: MAP kinase, Raf-1, and
RSK. Cell 68:104150
Wood SJ, Pritchard J, Sofroniew MV. 1990. Reexpression of nerve growth factor receptor
after axonal injury recapitulates a developmental event in motor neurons: differential
regulation when regeneration is allowed or
prevented. Eur. J. Neurosci. 2:65057
Woodruff NR, Neet KE. 1986. Beta nerve
growth factor binding to PC12 cells. Association kinetics and cooperative interactions.
Biochemistry 25:795666
Woolf C, Ma Q, Allchorne A, Poole S. 1996.
Peripheral cell types contributing to the hyperalgesic action of nerve growth factor in
inflammation. J. Neurosci. 16:271623
Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly
P, Winter J. 1994. Nerve growth factor
contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience
62:32731
Wooten MW, Seibenhener ML, Neidigh KB,
Vandenplas ML. 2000. Mapping of atypical
protein kinase C within the nerve growth factor signaling cascade: relationship to differentiation and survival of PC12 cells. Mol.
Cell. Biol. 20:4494504
Wooten MW, Seibenhener ML, Zhou G, Vandenplas ML, Tan TH. 1999. Overexpression of atypical PKC in PC12 cells enhances
NGF- responsiveness and survival through an
NF-kappaB dependent pathway. Cell Death
Differ. 6:75364
Wooten MW, Zhou G, Seibenhener ML, Coleman ES. 1994. A role for zeta protein kinase
C in nerve growth factor-induced differentiation of PC12 cells. Cell Growth Differ. 5:395
403
Wooten MW, Zhou G, Wooten MC, Seibenhener ML. 1997. Transport of protein kinase
C isoforms to the nucleus of PC12 cells by
nerve growth factor: association of atypical
zeta-PKC with the nuclear matrix. J. Neurosci. Res. 49:393403
Wyatt S, Shooter EM, Davies AM. 1990. Expression of the NGF receptor gene in sensory
neurons and their cutaneous targets prior to
and during innervation. Neuron 4:42127
Xiang J, Chao DT, Korsmeyer SJ. 1996. BAXinduced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Proc. Natl. Acad. Sci. USA 93:1455963
Xing J, Ginty DD, Greenberg ME. 1996. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated
CREB kinase. Science 273:95963
Xing J, Kornhauser JM, Xia Z, Thiele EA,
Greenberg ME. 1998. Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133
phosphorylation. Mol. Cell. Biol. 18:1946
55
Xue L, Murray JH, Tolkovsky AM. 2000.
The Ras/phosphatidylinositol 3-kinase and
Ras/ERK pathways function as independent
survival modules each of which inhibits a distinct apoptotic signaling pathway in sympathetic neurons. J. Biol. Chem. 275:881724
Yamashita H, Avraham S, Jiang S, Dikie I,
Avraham H. 1999a. The Csk homologous kinase associates with TrkA receptors and is
involved in neurite outgrowth of PC12 cells.
J. Biol. Chem. 274:1505965
Yamashita T, Tucker KL, Barde Y. 1999b. Neurotrophin binding to the p75 receptor modulates rho activity and axonal outgrowth. Neuron 24:58593
Yano H, Cong F, Birge RB, Goff SP, Chao MV.
2000. Association of the Abl tyrosine kinase
with the Trk nerve growth factor receptor. J.
Neurosci. Res. 59:35664
Yao R, Cooper GM. 1995. Requirement for
phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 267:20036
Ye X, Mehlen P, Rabizadeh S, VanArsdale T,
Zhang H, et al. 1999. TRAF family proteins
interact with the common neurotrophin receptor and modulate apoptosis induction. J.
Biol. Chem. 274:302028
P1: GDL
April 13, 2001
18:17
Annual Reviews
AR121-40


Yeo TT, Chua-Couzens J, Butcher LL, Bredesen DE, Cooper JD, et al. 1997. Absence
of p75NTR causes increased basal forebrain
cholinergic neuron size, choline acetyltransferase activity, and target innervation. J. Neurosci. 17:7594605
Yoon SO, Casaccia-Bonnefil P, Carter B, Chao
MV. 1998. Competitive signaling between
TrkA and p75 nerve growth factor receptors determines cell survival. J. Neurosci.
18:327381
York RD, Yao H, Dillon T, Ellig CL, Eckert SP,
et al. 1998. Rap1 mediates sustained MAP
kinase activation induced by nerve growth
factor. Nature 392:62226
Yoshida K, Gage FH. 1991. Fibroblast growth
factors stimulate nerve growth factor synthesis and secretion by astrocytes. Brain Res.
538:11826
Yoshida K, Gage FH. 1992. Cooperative regulation of nerve growth factor synthesis and
secretion in fibroblasts and astrocytes by fibroblast growth factor and other cytokines.
Brain Res. 569:1425
Yuen EC, Mobley WC. 1996. Therapeutic
1281
potential of neurotrophic factors for neurological disorders. Ann. Neurol. 40:346

54
Zafra F, Castren E, Thoenen H, Lindholm
D. 1991. Interplay between glutamate and
gamma-aminobutyric acid transmitter systems in the physiological regulation of brainderived neurotrophic factor and nerve growth
factor in hippocampal neurons. Proc. Natl.
Zha J, Harada H, Yang E, Jockel J, Korsmeyer
SJ. 1996. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell
87:61928
Zhao Y, Bjorbaek C, Moller DE. 1996. Regulation and interaction of pp90(rsk) isoforms
with mitogen-activated protein kinases. J.
Biol. Chem. 271:2977379
Zhao Y, Bjorbaek C, Weremowicz S, Morton
CC, Moller DE. 1995. RSK3 encodes a novel
pp90rsk isoform with a unique N-terminal
sequence: growth factor-stimulated kinase
function and nuclear translocation. Mol. Cell.
Biol. 15:435363
Annual Review of Neuroscience

Volume 24, 2001
CONTENTS

PDZ DOMAINS AND THE ORGANIZATION OF

SUPRAMOLECULAR COMPLEXES, Morgan Sheng, Carlo Sala
THE ROLE AND REGULATION OF ADENOSINE IN THE CENTRAL
NERVOUS SYSTEM, Thomas V. Dunwiddie, Susan A. Masino
LOCALIZATION AND GLOBALIZATION IN CONSCIOUS VISION,
S. Zeki
GLIAL CONTROL OF NEURONAL DEVELOPMENT, Greg Lemke
TOUCH AND GO: Decision-Making Mechanisms in Somatosensation,
Ranulfo Romo, Emilio Salinas
SYNAPTIC MODIFICATION BY CORRELATED ACTIVITY: Hebb''s
Postulate Revisited, Guo-qiang Bi, Mu-ming Poo
AN INTEGRATIVE THEORY OF PREFRONTAL CORTEX
FUNCTION, Earl K. Miller, Jonathan D. Cohen
THE PHYSIOLOGY OF STEREOPSIS, B. G. Cumming, G. C.
DeAngelis
PARANEOPLASTIC NEUROLOGIC DISEASE ANTIGENS: RNABinding Proteins and Signaling Proteins in Neuronal Degeneration, Kiran
Musunuru, Robert B. Darnell
ODOR ENCODING AS AN ACTIVE, DYNAMICAL PROCESS:
Experiments, Computation, and Theory, Gilles Laurent, Mark Stopfer,
Rainer W Friedrich, Misha I Rabinovich, Alexander Volkovskii, Henry
DI Abarbanel
PROTEIN SYNTHESIS AT SYNAPTIC SITES ON DENDRITES,
Oswald Steward, Erin M. Schuman
SIGNALING AND TRANSCRIPTIONAL MECHANISMS IN
PITUITARY DEVELOPMENT, Jeremy S. Dasen, Michael G. Rosenfeld
NEUROPEPTIDES AND THE INTEGRATION OF MOTOR
RESPONSES TO DEHYDRATION , Alan G. Watts
THE DEVELOPMENTAL BIOLOGY OF BRAIN TUMORS, Robert
Wechsler-Reya, Matthew P. Scott
TO EAT OR TO SLEEP? OREXIN IN THE REGULATION OF
FEEDING AND WAKEFULNESS, Jon T. Willie, Richard M. Chemelli,
Christopher M. Sinton, Masashi Yanagisawa
SPATIAL PROCESSING IN THE BRAIN: The Activity of Hippocampal
Place Cells, Phillip J. Best, Aaron M. White, Ali Minai
THE VANILLOID RECEPTOR: A Molecular Gateway to the Pain
Pathway, Michael J Caterina, David Julius
PRION DISEASES OF HUMANS AND ANIMALS: Their Causes and
Molecular Basis, John Collinge
VIKTOR HAMBURGER AND RITA LEVI-MONTALCINI: The Path to
the Discovery of Nerve Growth Factor, W. Maxwell Cowan
EARLY DAYS OF THE NERVE GROWTH FACTOR PROTEINS,
Eric M. Shooter
SEQUENTIAL ORGANIZATION OF MULTIPLE MOVEMENTS:
Involvement of Cortical Motor Areas, Jun Tanji
INFLUENCE OF DENDRITIC CONDUCTANCES ON THE INPUTOUTPUT PROPERTIES OF NEURONS, Alex Reyes
1
31
57
87
107
139
167
203
239
263
299
327
357
385
429
459
487
519
551
601
631
653

NEUROTROPHINS: Roles in Neuronal Development and Function, Eric

J Huang, Louis F Reichardt
CONTRIBUTIONS OF THE MEDULLARY RAPHE AND
VENTROMEDIAL RETICULAR REGION TO PAIN MODULATION
AND OTHER HOMEOSTATIC FUNCTIONS, Peggy Mason
ACTIVATION, DEACTIVATION, AND ADAPTATION IN
VERTEBRATE PHOTORECEPTOR CELLS, Marie E Burns, Denis A
Baylor
ACTIVITY-DEPENDENT SPINAL CORD PLASTICITY IN HEALTH
AND DISEASE, Jonathan R Wolpaw, Ann M Tennissen
QUANTITATIVE GENETICS AND MOUSE BEHAVIOR, Jeanne M
Wehner, Richard A Radcliffe, Barbara J Bowers
EARLY ANTERIOR/POSTERIOR PATTERNING OF THE
MIDBRAIN AND CEREBELLUM, Aimin Liu, Alexandra L Joyner
NEUROBIOLOGY OF PAVLOVIAN FEAR CONDITIONING, Stephen
Maren
{{alpha}}-LATROTOXIN AND ITS RECEPTORS: Neurexins and
CIRL/Latrophilins, Thomas C Sdhof
IMAGING AND CODING IN THE OLFACTORY SYSTEM, John S
Kauer, Joel White
THE ROLE OF THE CEREBELLUM IN VOLUNTARY EYE
MOVEMENTS, Farrel R Robinson, Albert F Fuchs
ROLE OF THE REELIN SIGNALING PATHWAY IN CENTRAL
NERVOUS SYSTEM DEVELOPMENT, Dennis S Rice, Tom Curran
HUMAN BRAIN MALFORMATIONS AND THEIR LESSONS FOR
NEURONAL MIGRATION, M Elizabeth Ross, Christopher A Walsh
MORPHOLOGICAL CHANGES IN DENDRITIC SPINES
ASSOCIATED WITH LONG-TERM SYNAPTIC PLASTICITY, Rafael
Yuste, Tobias Bonhoeffer
STOPPING TIME: The Genetics of Fly and Mouse Circadian Clocks,
Ravi Allada, Patrick Emery, Joseph S. Takahashi, Michael Rosbash
NEURODEGENERATIVE TAUOPATHIES, Virginia M-Y Lee, Michel
Goedert, John Q Trojanowski
MATERNAL CARE, GENE EXPRESSION, AND THE
TRANSMISSION OF INDIVIDUAL DIFFERENCES IN STRESS
REACTIVITY ACROSS GENERATIONS, Michael J Meaney
NATURAL IMAGE STATISTICS AND NEURAL
REPRESENTATION, Eero P Simoncelli, Bruno A Olshausen
Nerve Growth Factor Signaling, Neuroprotection, and Neural Repair,
Michael V Sofroniew, Charles L Howe, William C Mobley
FLIES, GENES, AND LEARNING, Scott Waddell, William G Quinn
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Annu. Rev. Neurosci. 2001. 24:1217281