Injury to the mature mammalian central nervous system (CNS) is often accompanied by permanent loss of function of the damaged neural circuits. The failure of injured CNS axons to regenerate is thought to be caused, in part, by neurite outgrowth inhibitory factors expressed in and around the lesion. These include several myelin associated inhibitors,
proteoglycans, and
tenascin-R. Recent studies have documented the presence of
class 3 semaphorins in fibroblast-like meningeal cells present in the core of the neural
scar formed following CNS injury.
Class 3 semaphorins display neurite growth-inhibitory effects on growing axons during embryonic development. The induction of the expression of
class 3 semaphorins in the neural
scar and the persistent expression of their receptors, the
neuropilins and plexins, by injured CNS neurons suggest that they contribute to the regenerative failure of CNS neurons.
Neuropilins are also expressed in the neural
scar in a subpopulation of meningeal fibroblast and in neurons in the vicinity of the
scar.
Semaphorin/
neuropilin signaling might therefore also be important for cell migration, angiogenis and neuronal cell death in or around neural
scars. In contrast to neurons in the CNS,
neuropilin/
plexin positive neurons in the PNS do display long distance regeneration following injury. Injured PNS neurons do not encounter a
semaphorin positive neural
scar. Furthermore,
Semaphorin 3A is downregulated in the regenerating spinal motor neurons themselves. This was accompanied by a transient upregulation of
Semaphorin 3A in the target muscle. These observations suggest that the injury induced regulation of
Semaphorin 3A in the PNS contributes to successful regeneration and target reinnervation. Future studies in genetically modified mice should provide more insight into the mechanisms by which
neuropilins and
semaphorins influence nervous system regeneration and degeneration.