Emerging roles for semaphorins in neural regeneration

Progressive axon outgrowth during neural development contrasts with the failure of regenerative neurite growth in the mature mammalian central nervous system (CNS). During neuroembryogenesis, spatiotemporal patterns of repellent and attractant activities in the vicinity of the growth cone favor neurite outgrowth. In the mature CNS, however, a relative balance between forces supporting and restricting axon growth has been established, only allowing subtle morphological changes in existing neuritic arbors and synapses. Following CNS injury, this balance shifts towards enhanced expression of growth-inhibiting molecules and diminished availability of their growth-promoting counterparts. Evidence is now emerging that the proteins governing developmental axon guidance critically contribute to the failure of injured central neurons to regenerate. As a first step toward elucidation of the role of chemorepulsive axon guidance signals in axonal regeneration, the effects of lesions of the central and peripheral nervous system on the expression of Semaphorin3A, the prototype and founding member of the semaphorin family of axon guidance signals, and of the Semaphorin3A receptor proteins neuropilin-1 and plexin-A1 have recently been examined. Here we review the first evidence indicating that (i) lesion-induced changes in the expression of chemorepulsive semaphorins relate to the success or failure of injured neurons to regenerate and (ii) semaphorins may represent important molecular signals controlling multiple aspects of the cellular response that follows CNS injury. In the future, genetic manipulation of the injury-induced changes in the availability of semaphorins and/or of their receptors will provide further insight into the mechanisms by which semaphorins influence neural regeneration.