Emerging roles for semaphorins in neural regeneration

Progressive axon outgrowth during neural development contrasts with the fai lure of regenerative neurite growth in the mature mammalian central nervous system (CNS). During neuroembryogenesis, spatiotemporal patterns of repell ent and attractant activities in the vicinity of the growth cone favor neur ite outgrowth. In the mature CNS, however, a relative balance between force s supporting and restricting axon growth has been established, only allowin g subtle morphological changes in existing neuritic arbors and synapses. Fo llowing CNS injury, this balance shifts towards enhanced expression of grow th-inhibiting molecules and diminished availability of their growth-promoti ng counterparts. Evidence is now emerging that the proteins governing devel opmental axon guidance critically contribute to the failure of injured cent ral neurons to regenerate. As a first step toward elucidation of the role o f chemorepulsive axon guidance signals in axonal regeneration, the effects of lesions of the central and peripheral nervous system on the expression o f Semaphorin3A, the prototype and founding member of the semaphorin family of axon guidance signals, and of the Semaphorin3A receptor proteins neuropi lin-1 and plexin-A1 have recently been examined. Here we review the first e vidence indicating that (i) lesion-induced changes in the expression of che morepulsive semaphorins relate to the success or failure of injured neurons to regenerate and (ii) semaphorins may represent important molecular signa ls controlling multiple aspects of the cellular response that follows CNS i njury. In the future, genetic manipulation of the injury-induced changes in the availability of semaphorins and/or of their receptors will provide fur ther insight into the mechanisms by which semaphorins influence neural rege neration. (C) 2001 Elsevier Science B.V. All rights reserved.