Review
Emerging roles for semaphorins in neural regeneration

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Abstract

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.

Introduction

Progressive axon outgrowth during neural development contrasts with the subtle structural alterations and the failure of regenerative neurite growth in the mature 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 axon guidance during development, critically contribute to the structural stability of mature neuronal networks and to the failure of injured central neurons to regenerate.

The discovery of several gene families containing members that can function as axon repellents has defined the concept of ‘guidance by repulsion’ at the molecular level (for review, see Ref. [177]). As has been shown for growth-promoting or attractive guidance cues, repulsive cues can either be short-range, surface-bound (i.e., contact repellents), or long-range, diffusible (i.e., chemorepellents) in nature. Recently characterized chemorepellents include ephrins, netrins, slits, and semaphorins (for review, see Refs. [34], [110], [157]). Curiously, some of these chemorepulsive axon guidance cues continue to be expressed in the mature rodent and human nervous system [46], [57], [58], [75], [94], [100], [196]. This sustained expression of chemorepulsive proteins during adulthood, as well as injury-induced recapitulation of their expression, may significantly influence the course of axonal regeneration.

As a first step toward elucidation of the role of chemorepulsive guidance signals in axonal regeneration, the effects of lesions to the CNS and peripheral nervous system (PNS) on the expression of Semaphorin3A (Sema3A), the prototype and founding member of the semaphorin family, and of the Sema3A receptor proteins neuropilin-1 and plexin-A1 have recently been examined. Here we review the first evidence indicating that lesion-induced changes in the expression of chemorepulsive axon guidance cues, i.e., semaphorins, may relate to the success or failure of injured neurons to regenerate. The first part of this review provides a concise summary of the role of axon growth inhibitors in CNS regeneration, followed by a brief description of recent advances in our understanding of the functional and biochemical properties of the semaphorins and their receptors. Both topics have been covered in more detail in several recent reviews [47], [73], [100], [181]. The second part of the review concentrates on a role for semaphorins, neuropilins and/or plexins in axonal regeneration in the adult mammalian nervous system. Although several lines of evidence indicate that semaphorins may belong to the factors that determine whether axonal regeneration will succeed or fail, further studies will be necessary to establish the causality of semaphorin function and regeneration failure. Therefore, in the third part of the review we discuss future directions for a functional analysis of semaphorin signaling in the injured nervous system.

Section snippets

Inhibitors of CNS regeneration

The successful attempts to facilitate CNS regeneration by providing mature neurons with a ‘permissive’ substrate indicate that environmental influences are of particular importance in the failure of central axons to regrow [35], [135]. In line with this, the glial-fibroblastic scar formed as a result of injury has long been considered as a mechanical constraint to elongating axons [187]. However, the inability of central sprouts to regenerate even in the presence of an ‘intact’ glial framework

Semaphorins and their receptors

Mature brain function is dependent on a precisely sculptured neuronal network. The complex wiring of the adult nervous system is controlled by an ordered series of guidance decisions during neural development. Within the last few years, it has become evident that semaphorins are critical in regulating many of these wiring events. Semaphorins comprise a large family of secreted and membrane-associated proteins, categorized into eight classes based on distinctive structural features [85], [97],

Chemorepulsive semaphorins in the neural scar

During neuroembryogenesis, the class 3 semaphorin Sema3A constitutes chemorepulsive barriers impermeable for axon growth. This is nicely illustrated in Sema3A−/− mice, which show aberrant axon extension into specific regions of the developing embryo, such as ventral spinal cord and lens, normally strictly avoided during pathfinding of Sema3A-responsive axons [9], [176]. As development progresses, neural Sema3A mRNA expression declines to become restricted to distinct populations of neurons in

Are regenerating fibers sensing semaphorins?

Injuries to fiber tracts originating from motor, sensory, olfactory neurons and retinal ganglion cells do either not affect or even induce neuronal expression of NP-1 and/or CRMP-2, a cytosolic protein necessary for Sema3A-induced growth cone collapse [52], [55], [107], [120], [121], [122], [126]. This may imply that these fiber populations can sense Sema3A as they attempt to regenerate. Unfortunately, the anti-NP-1 antibodies generated so far cannot be used to immunohistochemically detect

Semaphorins: molecular determinants of scar formation and/or neovascularization?

So far, the functional analysis of semaphorin-mediated control of nonneuronal cell behavior has been performed using model systems related to the intact immune or nervous system. Penetrating injuries to the mature CNS, however, lead to a partial recapitulation or induction of similar cellular events [47], [146]. A substantial body of evidence is now emerging suggesting that semaphorins and their receptors may represent important molecular signals controlling multiple aspects of the cellular

PNS lesions induce downregulation of Sema3A in injured motor neurons

Regenerating nerve fibers in the PNS eventually restore functional connections. Successful peripheral nerve regeneration is attributed to the initiation of a growth program and to the degradation or removal of inhibitory factors [51], [167]. The inactivation of inhibitors, such as those associated with myelin, appears to be essential for this regenerative success. For example, mice unable to remove myelin display poor peripheral nerve regeneration [19]. Furthermore, mice overexpressing MAG in

Clinical potentials

The destruction of nerve fiber connections in the mature human CNS has devastating consequences and produces lasting functional deficits. Pharmacological therapies that are currently used to treat spinal cord injury are primarily aimed at reducing secondary damage and do not promote regeneration of injured fiber tracts [14], [56]. The design of new therapeutic strategies to treat traumatic brain and spinal cord injury in human is therefore a major clinical challenge. It is, however, widely

Functional analysis of semaphorin signaling in the injured nervous system

During the past 10 years it has become evident that neurite outgrowth inhibitory molecules significantly influence the course of neural regeneration. Although the number of inhibitory proteins implicated in neural regeneration is still relatively small, future work will undoubtedly result in the identification of more regeneration-associated inhibitors, for example as a result of the emergence of new gene expression profiling techniques and the progression of the human genome project. Careful

Neutralizing neurite growth inhibitors from within

Although chemorepulsive semaphorins are likely to contribute to the inhibitory nature of the damaged CNS, it is evident that many additional inhibitory molecules are involved in rendering the injured brain and spinal cord nonpermissive for regenerative axon growth. Many of these inhibitory cues use mutual intracellular signal transduction mechanisms to exert their repulsive effects on (re)growing axons. Recent evidence suggests that this convergency may offer a unique opportunity to

Acknowledgements

We thank Dick Swaab for his comments on the manuscript and Fred de Winter for providing Fig. 1. This work was supported by a grant from the KNAW Vernieuwingsfonds and a NWO-GMW Pioneer Grant 030-94-142 (to J.V.).

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