| There is growing evidence that the molecular mechanisms that underlie the sculpting of
neuronal networks during development also apply to aspects of adult neuronal plasticity and
repair following injury. Much progress has been made in identifying molecules that regulate
axonal pathfinding but still little is known about how these molecules directly contribute to the
wiring and maintenance of complex neuronal connectivity in vivo. Using a genetic approach, our research aims
to elucidate the mechanisms that govern the assembly of specific neural networks. Understanding the
principles of network assembly will have important implications for the development of strategies aimed
to promote neural repair following trauma or disease.
Ongoing research projects are aimed to understand the role played by semaphorins and their receptors
in the developing, mature, and regenerating mammalian nervous system. The Semaphorins are a large
family of secreted and membrane bound proteins, several of which have been shown to participate in
the patterning of the developing nervous system. More than 25 members of the semaphorin gene family
have been identified and grouped into subclasses based on structural similarities. Class 3 semaphorins,
which include mammalian Sema3A, Sema3C, and Sema3F, are secreted proteins that function as potent chemorepellents
for specific classes of neurons. Sema3A is essential for neural development, since mice lacking this
secreted semaphorin exhibit severe defects in projections of cranial and spinal nerves. Recently, the
neuropilins and plexins have been identified as cell surface receptors for semaphorins. Neuropilins are
a small family of type 1 transmembrane proteins that bind secreted semaphorins with high affinity. Neuropilins
are essential components of the semaphorin receptor complex and impart functional specificity toward
different secreted semaphorin family members. We have found that neuropilin-2 is a receptor for the
secreted semaphorin Sema3F in cultured sympathetic neurons. To study neuropilin-2 signaling in vivo,
we have recently generated a null mutation at the mouse neuropilin-2 locus. Our initial analysis of
neuropilin-2 null mice revealed specific defects in cranial nerves and several major central nervous system fiber tracts
that normally express neuropilin-2. Interestingly, despite of many major defects in the nervous
system, many of the neuropilin-2 null mice survive into adulthood, providing a unique opportunity to
determine the role played by semaphorins and their receptors throughout development and in the mature nervous system.
Long-term goals of ongoing research projects include: (1) to elucidate the molecular mechanisms by
which axons are guided to their targets during neural development; (2) to apply this knowledge to systems
that model traumatic injury of the adult nervous system in order to develop means and strategies to
promote neuronal regeneration.
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Giger, R.J., Cloutier, J.-F., Sahay, A., Prinjha, R.K., Levengood, D.V., Moore, S.E.,
Pickering, S., Simmons, D., Rastan, S., Walsh, F.S., Kolodkin, A.L., Ginty, D.D., and Geppert, M.
(2000) Neuropilin-2 is required in vivo for selective axon guidance responses to secreted
semaphorins. Neuron 25:29-41.
Pasterkamp, R.J., Giger, R.J., Ruitenberg, M-J., Holtmaat, A.J.G.D., de Wit, J., de Winter, F.,
and Verhaagen, J. (1999) Expression of the gene encoding the chemorepellent semaphorin III is
induced in the fibroblast component of neural scar tissue formed following injuries of adult but
not neonatal CNS. MCN 13:143-166.
Giger, R.J., Urquhart, E.R., Gillerspie, S.K.H., Levengood, D.V., Ginty, D.D., and Kolodkin, A.L.
(1998) Neuropilin-2 is a receptor for Sema IV; insight into the structural basis of receptor function
and specificity. Neuron 21:1079-1092.
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