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Some landmarks of embryonic neural development include the birth and differentiation
of neurons from stem cell precursors, the migration of immature neurons from their
birthplaces in the embryo to their final positions, outgrowth of axons from neurons and
guidance of the motile growth cone through the embryo towards postsynaptic partners,
the generation of synapses between these axons and their postsynaptic partners, and
finally the lifelong changes in synapses which are thought to underlie learning and
memory.
Typically, these neurodevelopmental processes can be broadly divided into two classes:
activity-independent mechanisms and activity-dependent mechanisms. Activity-
independent mechanisms are generally believed to occur as hardwired processes
determined by genetic programs played out within individual neurons. These include
differentiation, migration and axon guidance to their initial target areas. These processes
are thought of as being independent of neural activity and sensory experience. Once
axons reach their target areas, activity-dependent mechanisms come into play. Neural
activity and sensory experience will mediate formation of new synapses, as well as
synaptic plasticity, which will be responsible for refinement of the nascent neural circuits.
The embryonic and fetal brains of all mammals develop in similar ways. The
embryonic spinal cord develops along common sequences and patterns. The nervous
system emerges from a simple elongated tube of cells, called the notochord. The
head (cranial) end of the embryonic tube expands and differentiates more robustly
(than does the spinal end) into several clusters of cells which emerge as the
forebrain (telencephalon and diencephalon), midbrain (mesencephalon) and
hindbrain (metencephalon and myelencephalon) portions.
Cell signaling is part of a complex system of communication that governs basic cellular
activities and coordinates cell actions.[1] The ability of cells to perceive and correctly
respond to their microenvironment is the basis of development, tissue repair, and
immunity as well as normal tissue homeostasis. Errors in cellular information processing
are responsible for diseases such as cancer, autoimmunity, and diabetes. By
understanding cell signaling, diseases may be treated effectively and, theoretically,
artificial tissues may be yielded.
Traditional work in biology has focused on studying individual parts of cell signaling
pathways. Systems biology research helps us to understand the underlying structure of
cell signaling networks and how changes in these networks may affect the transmission
and flow of information. Such networks are complex systems in their organization and
may exhibit a number of emergent properties including bistability and ultrasensitivity.
Analysis of cell signaling networks requires a combination of experimental and
theoretical approaches including the development and analysis of simulations and
modelling.
In animals, the brain is the control center of the central nervous system, responsible for
behavior. In mammals, the brain is located in the head, protected by the skull and close to
the primary sensory apparatus of vision, hearing, equilibrioception (balance), sense of
taste, and olfaction (smell).
While all vertebrates have a brain, most invertebrates have either a centralized brain or
collections of individual ganglia. Some animals such as cnidarians and echinoderms do
not have a centralized brain, and instead have a decentralized nervous system, while
animals such as sponges lack both a brain and nervous system entirely.
Brains can be extremely complex. For example, the human brain contains roughly
100 billion neurons, linked with up to 10,000 connections each.
chanism
Figure 5. Overview of Sonic hedgehog signaling. Click here for a more detailed diagram
Sonic hedgehog (SHH) is the best studied ligand of the vertebrate pathway. Most of what
is known about hedgehog signaling has been established by studying SHH. It is translated
as a ~45kDa precursor and undergoes autocatalytic processing to produce an ~20kDa N-
terminal signaling domain (referred to as SHH-N) and a ~25kDa C-terminal domain with
no known signaling role (1 on figure 5). During the cleavage, a cholesterol molecule is
added to the carboxyl end of the N-terminal domain, which is involved in trafficking,
secretion and receptor interaction of the ligand. SHH can signal in an autocrine fashion,
affecting the cells in which it is produced. Secretion and consequent paracrine hedgehog
signaling require the participation of Dispatched protein(2).
When SHH reaches its target cell, it binds to the Patched-1 (PTCH1) receptor(3). In the
absence of ligand, PTCH1 inhibits Smoothened (SMO), a downstream protein in the
pathway(4). It has been suggested that SMO is regulated by a small molecule, the cellular
localisation of which is controlled by PTCH[13]. PTCH1 has homology to Niemann-Pick
disease, type C1 (NPC1) that is known to transport lipophilic molecules across a
membrane. [14] PTCH1 has a sterol sensing domain (SSD), which has been shown to be
essential for suppression of Smo activity. [15]A current theory of how PTCH regulates
SMO is by removing oxysterols from SMO. PTCH acts like a sterol pump and remove
oxysterols that have been created by 7-dehydrocholesterol reductase. [16]Upon binding of
a Hh protein or a mutation in the SSD of PTCH the pump is turned off allowing
oxysterols to accumulate around SMO.
[edit] Role
Members of the hedgehog family play key roles in a wide variety of developmental
processes.[12] One of the best studied examples is the action of Sonic hedgehog during
development of the vertebrate limb. The classic experiments of Saunders and Gasseling
in 1968 on the development of the chick limb bud formed the basis of the morphogen
concept. They showed that identity of the digits in the chick limb was determined by a
diffusible factor produced by the zone of polarizing activity (ZPA), a small region of
tissue at the posterior margin of the limb. Mammalian development appeared to follow
the same pattern. This diffusible factor was later shown to be Sonic hedgehog. However,
precisely how SHH determines digit identity remained elusive until recently. The current
model, proposed by Harfe et al[23], states that both the concentration and the time of
exposure to SHH determines, which digit the tissue will develop into in the mouse
embryo (figure 6).
Members of the bone morphogenetic protein (BMP) family have been implicated in
multiple aspects of neural development in both the CNS and peripheral nervous system.
BMP ligands and receptors, as well as the BMP antagonist noggin, are expressed in the
developing cerebral cortex, making the BMPs likely candidates for regulating cortical
development. To define the role of these factors in the developing cerebral cortex, we
examined the effects of BMP2 and BMP4 on cortical cells in vitro. Cells were cultured
from embryonic day 13 (E13) and E16 rat cerebral cortex in the absence or presence of
different concentrations of fibroblast growth factor 2, a known regulator of cortical cell
proliferation and differentiation. At E13, the BMPs promoted cell death and inhibited
proliferation of cortical ventricular zone cells, resulting in the generation of fewer neurons
and no glia. At E16, the effects of the BMPs were more complex. Concentrations of
BMP2 in the range of 1-10 ng/ml promoted neuronal and astroglial differentiation and
inhibited oligodendroglial differentiation, whereas 100 ng/ml BMP2 promoted cell death
and inhibited proliferation. Addition of the BMP antagonist noggin promoted
oligodendrogliogenesis in vitro, demonstrating that endogenous BMP signaling
influences the differentiation of cortical cells in vitro. The distribution of BMP2 and
noggin within the developing cortex suggests that local concentrations of ligands and
antagonists define gradients of BMP signaling during corticogenesis. Together, these
results support the hypothesis that the BMPs and their antagonist noggin co-regulate
cortical cell fate and morphogenesis.
Frizzled Receptors and Wnt Signaling
Receptors
Frizzled receptors, like GPCRs, are transmembrane proteins that wind 7 times back and
forth through the plasma membrane.
Ligands
Their ligands are Wnt proteins. These get their name from two of the first to be
discovered, proteins encoded by
β-catenin molecules connect actin filaments to the cadherins that make up adherens
junctions that bind cells together.
Any excess β-catenin is quickly destroyed by a multiprotein degradation complex. (One
component is the protein encoded by the APC tumor suppressor gene.)
The degradation complex
Mechanism
• The binding of a Wnt ligand to Frizzled (done with the aid of cofactors) activates
Frizzled. This, in turn,
• activates a cytosolic protein called Dishevelled.
• Activated Dishevelled inhibits the β-catenin degradation complex so
• β-catenin escapes destruction by proteasomes and is free to enter the nucleus
where
• it binds to the promoters and/or enhancers of its target genes.
(Note the similarities to the strategy used by the NF-κB signaling pathway.)
Wnt-controlled gene expression plays many roles in embryonic development and
regeneration as well as regulating activities in the adult body.
Receptor
Ligands
Secreted hedgehog proteins (Hh) that diffuse to their targets. Mammals have three
hedgehog genes encoding three different receptors. However, hedgehog was first
identified in Drosophila, and the bristly phenotype produced by mutations in the gene
gave rise to the name.
Mechanism
Hedgehog signaling plays many important developmental roles in the animal kingdom.
For example,
Mutations or other sorts of regulatory errors in the hedgehog pathway are associated with
a number of birth defects as well as some cancers. Basal-cell carcinoma, the most
common skin cancer (and, in fact, the most common of all cancers in much of the world),
usually reveals mutations causing
• extra-high hedgehog or
• suppressed patched activity (both leading to elevated GLI activity).
Notch proteins are single-pass transmembrane glycoproteins. They are encoded by four
genes in vertebrates. However, the first notch gene was discovered in Drosophila where
its mutation produced notches in the wings.
Ligands
Their ligands are also single-pass transmembrane proteins. There are many of them and
often several versions within a family (such as the serrate and delta protein families).
Mechanism
When a cell bearing the ligand comes in contact with a cell displaying the notch receptor,
the external portion of notch is cleaved away from the cell surface (and engulfed by the
ligand-bearing cell by endocytosis). The internal portion of the notch receptor is cut away
from the interior of the plasma membrane and travels into the nucleus where it activates
transcription factors that turn the appropriate genes on (and off).
It would appear that proper development of virtually all organs (brain, pancreas, GI tract,
heart, blood vessels, mammary glands — to name a few) depends on notch signaling.
Notch signaling appears to be a mechanism by which one cell tells an adjacent cell which
path of differentiation to take (or not take).
Defects in notch signaling have been implicated in some cancers, e.g. melanoma.
Discovery
The Notch gene was discovered in 1917 by Thomas Hunt Morgan when it was first
noticed in a strain of the fruit fly Drosophila melanogaster with notches apparent in their
wingblades.[2][3] Its molecular analysis and sequencing was undertaken in the 1980s.[4][5]
[edit] Action
The Notch protein sits like a trigger spanning the cell membrane, with part of it inside
and part outside. Ligand proteins binding to the extracellular domain induce proteolytic
cleavage and release of the intracellular domain, which enters the cell nucleus to alter
gene expression.[6]
[edit] Functions
The Notch signaling pathway is important for cell-cell communication, which involves
gene regulation mechanisms that control multiple cell differentiation processes during
embryonic and adult life. Notch signaling also has a role in the following processes:
way
Maturation of the Notch receptor involves cleavage at the prospective extracellular side
during intracellular trafficking in the Golgi complex.[18] This results in a bipartite protein,
composed of a large extracellular domain linked to the smaller transmembrane and
intracellular domain. Binding of ligand promotes two proteolytic processing events; as a
result of proteolysis, the intracellular domain is liberated and can enter the nucleus to
engage other DNA-binding proteins and regulate gene expression.
Notch and most of its ligands are transmembrane proteins, so the cells expressing the
ligands typically need to be adjacent to the Notch expressing cell for signaling to occur.
[citation needed]
The Notch ligands are also single-pass transmembrane proteins and are
members of the DSL (Delta/Serrate/LAG-2) family of proteins. In Drosophila
melanogaster (the fruit fly) there are two ligands named Delta and Serrate. In mammals,
the corresponding names are Delta-like and Jagged. In mammals there are multiple Delta-
like and Jagged ligands, as well as possibly a variety of other ligands, such as
F3/contactin[16].
In the nematode Caenorhabditis elegans two genes encode homologous proteins, glp-1
and lin-12. There has been at least one report that suggests that some cells can send out
processes which allow signaling to occur between cells which are as much as four or five
cell diameters apart.[citation needed]
The Notch extracellular domain is composed primarily of small cysteine knot motifs
called EGF-like repeats.[19] Notch 1 for example has 36 of these repeats. Each EGF-like
repeat is approximately 40 amino acids, and its structure is defined largely by six
conserved cysteine residues that form three conserved disulfide bonds. Each EGF-like
repeat can be modified by O-linked glycans at specific sites.[20] An O-glucose sugar may
be added between the first and second conserved cysteine, and an O-fucose may be added
between the second and third conserved cysteine. These sugars are added by an as yet
unidentified O-glucosyltransferase, and GDP-fucose Protein O-fucosyltransferase 1
(POFUT1) respectively. The addition of O-fucose by POFUT1 is absolutely necessary for
Notch function, and without the enzyme to add O-fucose, all Notch proteins fail to
function properly. As yet, the manner in which the glycosylation of Notch affects
function is not completely understood.
The O-glucose on Notch can be further elongated to a trisaccharide with the addition of
two xylose sugars by xylosyltransferases, and the O-fucose can be elongated to a
tetrasaccharide by the ordered addition of an N-acetylglucosamine (GlcNAc) sugar by an
N-Acetylglucosaminyltransferase called Fringe, the addition of a galactose by a
galactosyltransferase, and the addition of a sialic acid by a sialyltransferase.[21]
To add another level of complexity, in mammals there are three Fringe GlcNAc-
transferases, named Lunatic Fringe, Manic Fringe, and Radical Fringe. These enzymes
are responsible for something called a "Fringe Effect" on Notch signaling.[22] If Fringe
adds a GlcNAc to the O-fucose sugar, then the subsequent addition of a galactose and
sialic acid will occur. In the presence of this tetrasaccharide, Notch signals strongly when
it interacts with the Delta ligand, but has markedly inhibited signaling when interacting
with the Jagged ligand.[23] The means by which this addition of sugar inhibits signaling
through one ligand, and potentiates signaling through another is not clearly understood.
[edit] Triggering
Because most ligands are also transmembrane proteins, the receptor is normally only
triggered from direct cell-to-cell contact. In this way, groups of cells can organise
themselves, such that if one cell expresses a given trait, this may be switched off in
neighbour cells by the inter-cellular Notch signal. In this way groups of cells influence
one another to make large structures.
The Notch cascade consists of Notch and Notch ligands, as well as intracellular proteins
transmitting the Notch signal to the cell's nucleus. The Notch/Lin-12/Glp-1 receptor
family[25] was found to be involved in the specification of cell fates during development
in Drosophila and C. elegans.[26] The Notch signaling pathway begins to inhibit new cell
growth when adolescence is reached, and keeps neural networks stable