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Editor’s Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral
fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more
information on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml.
In the developing nervous system, projec- ance cues are key mediators of this pro- deed, one member of the EphA family,
tion neurons extend axons tipped with cess, and are expressed in a high-to-low EphA7, is expressed in a high-to-low
motile growth cones that are responsible gradient from posterior to anterior tec- anterior-to-posterior gradient in the su-
for navigating to their appropriate targets tum. The receptor for ephrinA, named perior colliculus (SC) (Rashid et al.,
while avoiding inappropriate targets. In EphA, is expressed in a high-to-low gradi- 2005), the mammalian homolog of the
chicks and mammals, axons use a com- ent from temporal to nasal on retinal ax- tectum. EphA7 was not detected in retinal
plex strategy called delayed interstitial ons. Extension of collateral branches is axons. Furthermore, retinal ganglion cell
branching to accomplish this goal. Rather thought to be locally suppressed along the axons in culture avoid stripes of EphA7
than growing directly into the appropriate axon once a threshold level of EphA acti- laid down on the substrate, and nasal ax-
termination zone, axons grow past their vation is reached. Temporal axons, which ons in EphA7-deficient mice aberrantly
targets, and then selectively extend collat- express a higher concentration of EphA project to a second, anterior termination
eral branches onto and around their tar- receptors, require less ephrinA to sup- zone.
gets. Finally, exuberant branches and the press branching than nasal axons, and Although the expression patterns eph-
primary axon are pruned, leaving the ap- therefore branch anterior to their nasal rinA and EphA7 are compatible with a
propriate connections in the final termi- counterparts. While this model explains model in which ephrinA acts as a receptor
nation zone. why temporal axons only branch in ante- on retinal axons, unlike the transmem-
How do axons restrict their branching rior tectum, it does not explain why nasal brane ephrinB proteins, ephrinAs are GPI
to their appropriate termination zone? axons preferentially branch in posterior linked, lacking an intracellular domain.
The retinotectal system has been studied tectum—a single branch-suppressing gra- This makes it unlikely that they act as a
extensively to address this question (for dient would lead nasal axons to branch genuine receptor. How, then, do ephrinAs
review, see McLaughlin and O’Leary,
along the entire anteroposterior extent of transduce extracellular EphA7 gradients
2005). Retinal ganglion cell (RGC) axons
the tectum. Therefore a second gradient is into spatially instructive intracellular sig-
enter the anterior tectum and project to
necessary to explain the suppression of nals? Marler et al. (2008) address this
the posterior tectum. Axons from tempo-
nasal axon branching in anterior tectum. question in a recent article in The Journal
ral retina preferentially branch into the
Interestingly, retinal axons express of Neuroscience.
anterior tectum, while axons from nasal
ephrinA5 in addition to EphA. In contrast Marler et al. (2008) hypothesized that
retina branch into the posterior tectum. It
is thought that axons achieve this selective to EphA, which is more highly expressed ephrinA might act indirectly, as a corecep-
branching by responding to gradients of on temporal axons, the ephrinA gradient tor for a second signaling pathway. TrkB,
axon guidance molecules that suppress is highest on nasal axons and lowest on a receptor for brain-derived neurotrophic
branching at inappropriate locations. temporal axons. This countergradient of factor (BDNF), was a good candidate
Members of the ephrinA family of guid- ephrinA suggested that ephrinA might act since BDNF promotes branching of RGC
as a receptor on retinal axons rather than a axons. Both overexpression of ephrinA5
ligand. Such a role has been demonstrated and treatment with BDNF increased the
Received Jan. 15, 2009; revised Feb. 20, 2009; accepted Feb. 23, 2009.
This work was supported by National Research Service Award
in the closely related ephrinB and EphB number of axon branches in retinal axons
GM801642 to B.I.H. and a Herman I. Shapiro Fellowship to L.L. family proteins, which have both been in vitro [Marler et al. (2008), their Fig.
*B.I.H. and L.L. contributed equally to this work. shown to act as ligand and receptor 1 F, G]. Interestingly, when BDNF was ap-
Correspondence should be addressed to either B. Ian Hutchins or Li Li, (McLaughlin et al., 2003). For this to be plied to the neurons that overexpressed
Neuroscience Training Program, 1300 University Avenue, Madison, WI
53706, E-mail: bihutchins@wisc.edu or lli5@wisc.edu.
the case, EphA should be expressed in a ephrinA5, axon branching was further in-
DOI:10.1523/JNEUROSCI.0238-09.2009 gradient in the tectum, and axons should creased [Marler et al. (2008), their Fig.
Copyright©2009SocietyforNeuroscience 0270-6474/09/294329-03$15.00/0 respond to EphA as a guidance cue. In- 1 F, G]. Although EphA7-Fc, which acti-
4330 • J. Neurosci., April 8, 2009 • 29(14):4329 – 4331 Hutchins and Li • Journal Club
ons shifted or expanded to slightly more lead to less severe guidance errors. One mediates ephrin-A reverse signaling re-
anterior positions (Lim et al., 2008). If way to test between the two models dis- quired for axon repulsion and mapping.
EphA7 acts via p75 to suppress branching, cussed here (Fig. 1) would be to overex- Neuron 59:746 –758.
Marler KJ, Becker-Barroso E, Martínez A, Llovera
then similar guidance errors should be press p75 in nasal RGCs and treat them
M, Wentzel C, Poopalasundaram S, Hindges
observed in both knock-outs. with EphA7 in the absence of BDNF. If R, Soriano E, Comella J, Drescher U (2008)
If the results from p75-deficient mice EphA7/ephrinA/p75 actively suppresses A TrkB/EphrinA interaction controls retinal
do not support the hypothesis that branching, there should be fewer axon branching and synaptogenesis. J Neuro-
EphA7/ephrinA actively suppresses branches per axon for cells overexpressing sci 28:12700 –12712.
branching, how do they fit with our alter- p75 compared with controls, in the pres- McLaughlin T, O’Leary DD (2005) Molecular
native model? A recent study by Singh et ence of EphA7. On the other hand, if gradients and development of retinotopic
al. (2008) showed that p75 inhibits the EphA7/ephrinA/p75 merely inhibits maps. Annu Rev Neurosci 28:327–355.
Trk signaling pathway, including the PI3 BDNF/TrkB signaling once activated, McLaughlin T, Hindges R, Yates PA, O’Leary
kinase pathway in peripheral axons. It is then there should be no difference be- DD (2003) Bifunctional action of
ephrin-B1 as a repellent and attractant to
possible that p75 activation does not re- tween these two groups.
control bidirectional branch extension in
duce branching per se, but rather inhibits Although much still needs to be done dorsal-ventral retinotopic mapping. Devel-
BDNF/TrkB signaling. In this case, re- to fully understand the mechanisms of opment 130:2407–2418.
moving EphA7 from the tectum would retinotopic mapping, the results by Mar- Rashid T, Upton AL, Blentic A, Ciossek T, Knöll
disinhibit the branch-promoting eph- ler et al. (2008) offer important insights B, Thompson ID, Drescher U (2005) Op-
rinA/TrkB interaction and would also re- into complex interactions between differ- posing gradients of ephrin-As and EphA7 in
lieve the downstream inhibition of PI3 ki- ent guidance cues and bidirectional sig- the superior colliculus are essential for topo-
nase from EphA7/ephrinA/p75 signaling. naling of EphAs/ephrinAs by providing graphic mapping in the mammalian visual
This would lead to dramatic guidance er- the first evidence that EphA/ephrinA in- system. Neuron 47:57– 69.
rors to anterior tectum/SC, as seen in the teracts with BDNF/TrkB signaling to reg- Segal RA (2003) Selectivity in neurotrophin sig-
naling: theme and variations. Annu Rev Neu-
EphA7 knock-out mouse (Rashid et al., ulate axon branching in the retinotectal
rosci 26:299 –330.
2005). In contrast, removing p75 from system. Singh KK, Park KJ, Hong EJ, Kramer BM, Green-
RGC axons would relieve inhibition of berg ME, Kaplan DR, Miller FD (2008) De-
signaling downstream of BDNF/TrkB but References velopmental axon pruning mediated by
would not disinhibit the ephrinA/TrkB Lim YS, McLaughlin T, Sung TC, Santiago A, BDNF-p75NTR-dependent axon degenera-
interaction. This might be expected to Lee KF, O’Leary DD (2008) p75(NTR) tion. Nat Neurosci 11:649 – 658.