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Neuropilin and Class 3 Semaphorins in Nervous System Regeneration

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Summary

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, angiogenesis 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.

Introduction

Maturation of the mammalian central nervous system is accompanied by a significant decline of its spontaneous capacity to regenerate following injury. In contrast, neurons of the adult mammalian peripheral nervous system (PNS) do retain their regenerative capacity throughout life. The balance between growth-supporting and growth-inhibiting factors, expressed by neurons and non-neuronal cells, is thought to determine whether regeneration occurs successfully or fails.1-3

Molecules that inhibit regenerative axonal outgrowth are present in CNS myelin and in the neural scar that is formed at the site of the lesion.4,5 Following a CNS lesion induction of the expression of growth-inhibitory proteins in the scar is regarded as an important cause underlying regenerative failure in the adult mammalian CNS. The discovery that repulsive axon guidance cues, including members of the ephrin, netrin, Slit and semaphorin family, are also expressed in the mature nervous system1-3 has led to speculation on possible roles of these proteins in plasticity and regeneration during adulthood.6-9 Although the levels of these molecules often decline during maturation, many of these proteins and their receptors are persistently expressed during adulthood.9-14 The recent reports of injury-induced expression of Semaphorin 3A (Sema3A) and Ephrin B3 (EphB3) at the spinal cord lesion site,15-17 together with the downregulation of Sema3A in motor neurons and the upregulation in terminal Schwann cells after PNS injury,18-20 strongly suggest that these repulsive axon guidance molecules are involved in neuronal regeneration.

Here we review putative roles of semaphorins and their receptors neuropilins and plexins in the damaged central and peripheral rodent nervous system.

General Features of CNS Regeneration

Following transection of an axon in the CNS, the portion of the axon distal to the lesion starts to degenerate and will subsequently be removed by macrophages and activated microglia. The injured neuron will either survive and often atrophy when the axon is cut far from the cell body, or die, when the axon is cut near the cell body. At the site of the lesion, a glial scar will be formed. The glial scar consists of two main components. The center of the injury site is invaded by meningeal cells, vascular endothelial cells and macrophages. Around the site of the injury a halo of reactive gliosis, containing astrocytes, oligodendrocyte precursors and microglia cells is formed.5,21,22 Although most CNS axon populations do form sprouts near the lesion site, these sprouts are not able to grow across the lesion and thus do not re-innervate their distal target cells.23-27

Several studies have shown that CNS axons have the capability to regenerate over long distances when provided with a suitable substrate, like a piece of peripheral nerve, Schwann cells grafts, olfactory ensheeting glia cells or fetal nervous tissue.28-32 This suggests that environmental factors critically contribute to the success of the regeneration process. Successful regeneration of CNS axons into growth-permissive grafts demonstrates their capability to regenerate over relatively long distances. Re-growing CNS axons do stop dead however as soon as they reach the distal end of the graft, and will not reenter CNS tissue. Thus, re-growth of CNS axons through a graft does not lead to the reestablishment of functional neuronal connections.

Further evidence of the inhibitory nature of CNS tissue has been derived from studies on regenerating dorsal root ganglion (DRG) cells. When the central projection of these PNS neurons is crushed between the DRG and the spinal cord, the injured axons will regenerate towards the spinal cord as long as they are in a PNS environment but stop growing as soon as they reach the CNS environment of the spinal cord.33-35

To date several inhibitory molecules have been identified in adult CNS myelin, including Nogo36,37(formerly known as NI-250) and myelin-associated glycoprotein (MAG).38,39 Antibodies directed to Nogo partially neutralize the myelin-associated inhibition of axonal growth in vitro and in vivo.37,40-42 Furthermore, CNS injury results in enhanced expression of neurite outgrowth inhibiting extracellular matrix proteins, like chondroitin sulphate proteoglycans (CSPG)43-46 and tenascin,47-51 by reactive astrocytes and other scar-associated cells at the injury site.2,5,22,52 The recent discovery that chemorepulsive proteins, like EphB317 and Sema3A,16,53 known to repel specific developing populations of axons, are expressed at high levels in the injured CNS, provides the first indication that regeneration in the adult CNS might be impaired due to the expression of these repulsive developmental guidance cues.

Semaphorin and Neuropilin in the Intact and Injured Olfactory System

Neuropilin-1 (NRP1) was originally discovered in Xenopus (see chapter 1). Based on its cellular distribution, NRP1 was thought to be an important axon guidance molecule for primary olfactory neurons.54 Following the discovery that NRP1 is an essential component of the receptor for Sema3A,6,55 extensive studies have been carried out to relate NRP1 and Sema3A expression to axonal guidance events in the developing, adult and regenerating rodent olfactory system.9,56-62

Developing Olfactory System

During early embryonic development olfactory receptor neurons (ORN) extend fibers to the telencephalic vesicle before the formation of their target structure, the olfactory bulb, has started. The arriving ORN axons halt for several days just outside the developing CNS and appear to have a role in inducing the formation of the olfactory bulb.63 Primary olfactory nerve fibers start to enter the developing olfactory bulb approximately two days after they have arrived at the rim of the telencephalic vesicle.57,64 Based on the temporal and spatial expression pattern of Sema3A at the periphery of the rat telencephalic vesicle Giger et al9 suggested the involvement of Sema3A in this pausing behavior of the developing primary olfactory neurites. Renzi et al58 showed that overexpression of a dominant-negative NRP1 that blocks Sema3A-mediated signaling in primary olfactory axons induces premature ingrowth into the telencephalic vesicle. This study demonstrated that Sema3A indeed governs the pausing of ORN axons at the rim of the telencephalic vesicle.

Analysis of NRP1 and Sema3A expression patterns later on in development of the olfactory system revealed a striking complementary relationship. Growing NRP1 positive sensory fibers avoid Sema3A expressing non-neuronal cells in the nerve layer tracts, resulting in region specific innervation of the olfactory bulb.61 This is in line with the responsiveness of cultured embryonic ORN to Sema3A.57,62 In the absence of Sema3A, like in the Sema3A null mutant mice, many NRP1 axon are misrouted, and form atypically located glomeruli.61

Sema3A expression in deeper layers of the olfactory bulb, by mitral, periglomerular and tufted cells is thought to prevent overshoot of most primary olfactory axons into extra-glomerular layers of the bulb.9 However, some primary olfactory axons appear to escape this mechanism and do elaborate transient axons into the external plexiform layer.65 During embryonic development Sema3A expression is also reported in the olfactory epithelium itself, although its function is not clear.57,58,62 The relatively low levels of Sema3A found in the embryonic and neonatal olfactory epithelium may push the primary olfactory axons out of the epithelium and towards its target structure, the main olfactory bulb.

Adult Olfactory System

Adult primary olfactory receptor neurons are continuously replaced during adulthood.66,67 Newly formed olfactory neurons display long distance axon growth towards the olfactory bulb, where they form synapses on their target neurons, the mitral cells and juxtaglomerular cells (Figure 1 and 2). Localization studies showed that NRP1 and collapsin response mediator protein 2 mRNA (CRMP-2; intracellular molecule involved in Sema3A induced growth cone collapse68) are predominantly expressed in differentiating and young primary olfactory neurons, suggesting a role for Sema3A in axon pathfinding of these newborn neurons during adulthood59 (Figure 1A and 1B). In line with this both NRP1 and the cell adhesion molecule L1 (thought to be involved in NRP1 signaling,69 see chapter 7 of this issue) are present on the primary olfactory axons extending towards the olfactory bulb64 (Figure 1I). An attractive idea is that Sema3A released by dendrites of mitral and tufted cells may act as a stop signal for growing ORN axons and allows them to establish synaptic contacts within the glomeruli (Figure 1I and Figure 2; box 2). High levels of Sema3A mRNA expression observed in adult mitral and tufted cells and the responsiveness of cultured ORN towards Sema3A during development supports this hypothesis.56,57,59,60

Figure 1. Neuropilin and semaphorin expression in the intact and injured olfactory system.

Figure 1

Neuropilin and semaphorin expression in the intact and injured olfactory system. (A-H) Horizontal sections through the olfactory epithelium of unlesioned adult rats (A-D) and bulbectomized rats (30 days post-lesion, E-F) were stained for NRP1 mRNA (A, (more...)

Figure 2. Proposed roles of Neuropilin-Semaphorin 3A signaling in the intact and injured olfactory system.

Figure 2

Proposed roles of Neuropilin-Semaphorin 3A signaling in the intact and injured olfactory system. Schematic drawing showing the intact (right side) and the lesioned (left side) olfactory system. Inserts of boxes 1 and 2 are higher magnifications of the (more...)

Regenerating Olfactory System

During adulthood the primary olfactory system retains a remarkable regenerative response, but ORN axons do not grow through a glial scar and do not reach the forebrain70 (Figure 1 and Figure 2; box 1). Regenerating ORN axons can, however, reach and enter the forebrain in neonatal mice following bulbectomy. In neonatal mice no inhibiting glial scar is formed.67 In adult animals, removal of the olfactory bulb induces neurogenesis in the olfactory epithelium66,71-73 and the formation of a neural scar in the bulbar cavity. The neural scar in the bulbar cavity prevents regeneration of newly formed primary olfactory axons into the undamaged adult CNS.74,75 Analysis of the CNS scar formed following bulbectomy revealed the presence of high levels of Sema3A transcripts in fibroblast-like cells (Figure 1J and 1K). Encapsulation of the regenerating NRP1-positive axon bundles by these Sema3A-positive cells is likely to contribute to the inhibition of their growth, thereby preventing them from entering the forebrain.59

Neuropilin Ligands Are Expressed by the Fibroblast Component of Neural CNS Scars

Like bulbectomy, transection of the lateral olfactory tract (LOT) in the mature brain results in the formation of a neural scar. The LOT contains mainly mitral cell axons which project to the olfactory cortex. Despite the upregulation of growth associated proteins, like B-50/GAP-43,76 mitral cell axons are not able to grow across the neural scar.24-27 The cell bodies of the mitral cells, located in the main olfactory bulb, continue to express NRP1 following transection of the LOT, suggesting an ongoing sensitivity of adult injured mitral cell axons for Sema3A. In contrast, NRP1-positive mitral cells do extend axons through the lesion site following LOT lesions in neonatal rats.16,24-27 A striking difference between neonatal lesions and lesions during adulthood is the infiltration of numerous Sema3A-expressing meningeal fibroblasts that form the core of the adult neural scar. These cells are virtually absent in the neonatal scar.16,77 Neural scars formed following stab wound lesions into other regions of the adult CNS, such as cerebral cortex, perforant pathway and spinal cord, are all characterized by the infiltration of Sema3A-positive meningeal fibroblasts.16

Recent examination of the neural scar formed following complete spinal cord transection revealed the expression of all other class 3 semaphorin family members78 (Figure 3E and 3D). Besides Sema3A, meningeal fibroblasts that penetrate the lesion displayed moderate-to-high expression levels of Sema3B, Sema3C, Sema3E and Sema3F, which are all known to exhibit repulsive properties for subpopulations of axons during neural development.69,79-81 Continuous expression of the class 3 semaphorin receptor components, NRP1, NRP2 and Plexin-A1 (Plex-A1), by the two major descending motor pathways, the corticospinal tract (Figure 3A-3C) and rubrospinal tract (CST and RST respectively), following spinal cord injury, renders these axon tracts potentially sensitive to scar-derived semaphorins. In line with this, most descending spinal cord fibers fail to enter the semaphorin-positive portion of the spinal neural scar. Likewise, Pasterkamp et al.15 have shown that the ascending central projections of dorsal root ganglion cells also do not penetrate Sema3A-positive regions of the scar that is formed after transection of the spinal cord dorsal column.

Figure 3. Neuropilin and Semaphorin expression following complete spinal cord transection.

Figure 3

Neuropilin and Semaphorin expression following complete spinal cord transection. (A-C) Transverse sections through the motor cortex of non-lesioned adult rats were subjected to in situ hybridization for NRP1, NRP2 and CRMP-2. Cell bodies that give rise (more...)

In summary, NRP1 as well as NRP2 expressing fibers do not penetrate class 3 semaphorin containing regions in the CNS lesion site (Figure 3I). Therefore, injury induced expression of developmentally important chemorepulsive axon guidance molecules, like semaphorins, may contribute significantly to the non-permissive nature of CNS scars.

Neuropilins Are Expressed at the CNS Lesion Site

Other functions of class 3 semaphorins in the neural CNS scar should be considered. Recently, it has been reported that not only class 3 semaphorins are expressed in the neural scar but also their receptors, the neuropilins16,53,82 (Figure 3F and 3G). Vascular endothelial growth factor (VEGF), which also binds to neuropilins,83 is also induced at CNS injury sites.82,84 The presence of ligands as well as receptor molecules in non-neuronal cells of the CNS scar invites the speculation that neuropilin-semaphorin/VEGF signaling plays a role in various cellular responses during formation of the neural scar. In vitro studies have revealed that competition between Sema3A and VEGF-165 influences cell survival, migration and proliferation.85,86

Migration

In vitro neural crest and endothelial cells are repelled by Sema3A, a process that is mediated via NRP1.85,87 Sema3C null mutant mice suffer from defects in neural crest cell migration.88 Furthermore, Sema3C, Sema3E and Sema3F are associated with invasive and metastasizing features of tumor cells.89-92 It is therefore conceivable that co-expression of neuropilins and semaphorins in the neural scar contributes to cell motility. The temporal expression profile of class 3 semaphorins in meningeal fibroblasts correlates strongly with the massive infiltration of these cells into the scar observed following penetrating injuries of the adult CNS. Following similar injuries in the neonatal brain no semaphorin expression was detected,16 which is in line with the absence of migrating meningeal fibroblasts in neonatal lesions.77

Meningeal fibroblast invasion of the CNS injury site is not only age dependent, but also dependent on lesion type.5 In non-penetrating injuries, like spinal cord contusion lesions, semaphorin expression is restricted to cells in the swollen meningeal sheet present at the site of the contusion lesion.78 This can be explained by the limited infiltration of meningeal fibroblasts into a contusion lesion site.5,93 Although causal evidence remains to be gathered, it is not unlikely that meningeal cell motility during neural scar formation is affected by secreted semaphorins and neuropilins.

Angiogenesis

Studies in genetically manipulated animals demonstrated the importance of neuropilin signaling for blood vessel formation. Both overexpression and absence of NRP1 during development lead to an abnormal cardio-vascular system.94,95 Additionally, malformations can be observed in the cardio-vascular system of Sema3A knockout mice.96 Furthermore, Soker et al83 identified NRP1 as an isoform-specific receptor for VEGF-165 (vascular endothelial growth factor-165) which mediates mitogenic activities on endothelial cells. In vitro studies revealed inhibitory effects of Sema3A on endothelial cell motility and microvessel sprouting.85 It is therefore conceivable that neovascularization observed in and around the CNS lesion area97,98 may be modulated by injury-induced expression of neuropilins, VEGF and class 3 semaphorins.

Incisions in the lateral funiculus of the spinal cord showed that vascular endothelial growth factor and its receptors, VEGFR1 (1fms-like tyrosine kinase 1, Flt-1) and VEGFR2 (fetal liver kinase 1, Flk-1) and co-receptor NRP1 are indeed induced in structures correlated with or near vessels in the lesion area82(Figure 3H).

Pasterkamp et al16 also observed NRP1 expression on the surface of blood vessels in the neural scar formed following injuries in other CNS brain areas. Furthermore, focal ischemia induces the formation of new blood vessels mainly in the areas where a temporal upregulation of NRP1 is observed in endothelial cells.99 In vitro studies have shown that Sema3A and VEGF-165 compete for the NRP1 binding site,85,86 but to date it is not known if this competition favors blood vessel formation at the CNS injury site.

Cell Death

Injury in the adult CNS often results in secondary cell death in the neural tissue surrounding the lesion. Especially following spinal cord injury, progressive secondary cell death extending to proximal and distal directions, has been observed. 100,101 Several studies have reported on the participation of neuropilin/semaphorin signaling in processes resulting in cell death.86,102-104

Dopamine-induced apoptosis in neurons is accompanied by a synchronized induction of Sema3A and CRMP. This can be blocked by antibodies against Sema3A or the receptor NRP1, indicating that Sema3A/NRP1 signaling is involved in apoptosis.102 Sema3A also induces apoptotic cell death of NGF-dependent sensory neurons.103 Furthermore, Fujita and colleagues showed that middle cerebral artery occlusion in the adult rat brain induces upregulation of NRP1, NRP2 and Sema3A in neurons of the directly affected area within the three days prior to their death.104 Progressive secondary cell death is a major problem in (especially) spinal cord regeneration and may be facilitated by neuropilins and semaphorins expressed in and around the lesion site.

Neuropilin/Semaphorin Regulation in Rat Models for Status Epilepticus

Organotypic cocultures have revealed that embryonic pieces of entorhinal cortex (EC) repel hippocampal axons. This effect can be blocked by NRP1 antibodies or mimicked by Sema3A secreting COS cell aggregates.105-107 Since neuropilin-semaphorin interactions in the developing nervous system are essential for the formation of a correct neural network,96,108-110 disturbances here in might be involved in the formation of aberrant neural circuits in the diseased brain. Studies in different rat models for status epilepticus (SE) have revealed changes in neuropilin and/or semaphorin expression prior to axon sprouting and synaptic reorganizations observed in these models.111-113

In the temporal lobe epilepsy (TLE) model status epilepticus is induced by electrical stimulation of the axons projecting from EC to the molecular layer (ML) of the dentate gyrus, the so called angular bundle (Figure 4). This results in spontaneous seizures after a latent period of 1-2 weeks which is preceded by sprouting of the granule cell axons (mossy fibers) into the ML. Transient downregulation of Sema3A expression was observed in stellate cells of the EC following induction of SE.111 Furthermore, GAP-43 was upregulated in the granule cells themselves.114-117 The loss of a repulsive molecule for mossy fibers and the upregulation of intrinsic growth molecules could allow mossy fibers to penetrate into the ML. Although the lack of Sema3A protein secretion in the OML has as yet not been shown, it is likely to occur since up regulation of GAP-43 by itself is not sufficient to induce mossy fiber sprouting.111 Axonal sprouting of CA1 pyramidal cells in kainic acid induced SE is not only accompanied by reduction in expression of the ligands Sema3A and Sema3C in these cells, but also by a decline in their NRP1 and NRP2 expression.112,113

Figure 4. Neuropilin and Semaphorin 3A expression in the entorhinal-hippocampal system.

Figure 4

Neuropilin and Semaphorin 3A expression in the entorhinal-hippocampal system. (A-D) Horizontal sections through the adult rat brain. In situ hybridization for NRP1, NRP2 and Sema3A mRNA in the entorhinal-hippocampal system. NRP1 expression is strong in (more...)

Induced temporary changes in the expression levels of outgrowth-promoting and outgrowth-restricting molecules may contribute to processes like reactive sprouting in the epileptic hippocampus. Moreover, it suggests the involvement of these molecules in structural plasticity in the intact adult brain. This notion is further supported by the persistent expression of axon growth regulating signaling proteins, like neuropilins, plexins and semaphorins, in adult brain structures, typically associated with plasticity, such as the olfactory-hippocampal system.56,118

General Aspects of PNS Regeneration

Damage to the adult mammalian PNS is marked by relatively successful regeneration, including functional recovery of motor and sensory functions.119,120 Transection or crush of peripheral axons results in degeneration of the axon stump and the myelin sheath distal to the lesion. Removal of axonal and myelin debris by macrophages and Schwann cells is essential for successful regeneration.1,3,121,122 Schwann cells start to divide and initiate the expression of several neurotrophic factors, including NGF and BDNF.123,124 Furthermore, they change their cell surface by increasing the expression of adhesion molecules, like N-CAM, N-cadherin, and the low affinity receptor (P75) for neurotrophins.125,126

The success of regeneration in the peripheral nerve largely depends on the maintenance of basal lamina sheath. Normally these sheaths surround the axon/Schwann cell units, and are important during regeneration for appropriate guidance of regenerating axons back towards their original targets. Only after severe injury of a peripheral nerve, involving the destruction of the basal lamina and the Schwann cell, a non permissive fibroblastic scar will be formed.

In contrast to axotomized CNS neurons, injured PNS neurons are able to initiate and maintain a gene expression program that promotes axon outgrowth during the time they regenerate. Upregulation of growth-associated proteins, immediate early genes and transcription factors, such as GAP-43/B-50,120,127 tubulin and actin,128 c-fos, c-jun and KROX 24,129-131 are thought to increase the growth potential of lesioned PNS neurons.

Neuropilin/Semaphorin Regulation in the Injured PNS

Facial and spinal motor neurons continuously express NRP1 and Sema3A during adulthood. This indicates that their axons are persistently sensitive to semaphorins, which in turn are continuously present in their vicinity. In contrast to lesions in the CNS, a crush or transection of the peripheral nerve does not induce Sema3A expression at the site of the lesion. In addition, peripheral nerve in (motor) neurons (Figure 5A) while NRP1 and Plex-A1 mRNA levels remain unchanged or are slightly upregulated18,132 (Figure 5C and 5D). The Sema3A messenger levels stay low during the time injured neurons extend regenerating axons towards their target. The period of down regulation is closely related to the temporal upregulation of the growth associated protein B-50/GAP-43 (Figure 5B). Target re-innervation appears to be essential to restore Sema3A expression, since prevention of regeneration by nerve transection and back-ligation of the proximal nerve stump results in persistent downregulation of Sema3A expression.18

Figure 5. Expression of Sema3A and its receptor components following sciatic nerve crush.

Figure 5

Expression of Sema3A and its receptor components following sciatic nerve crush. (A-D) Serial transverse sections through the rat L5 spinal cord were subjected to in situ hybridization for Sema3A, B50/GAP-43, NRP1 and Plex-A1 mRNA. At 7 days following (more...)

The biological significance of co-expression of NRP1/PlexA1 complex and Sema3A in the same neuron is currently not understood. One hypothesis states that the regeneration related down regulation of Sema3A is necessary to prevent an inhibitory effect of secreted Sema3A on its own and/or neighboring axon tips. A similar situation is observed in the developing chick embryo, where growing spinal motor neurons express Sema3A, and at the same time are repelled by this molecule in an in vitro assay.133 Co-culture studies have demonstrated that rat embryonic motor neurons are responsive to Sema3A.134

An alternative hypothesis, concerning co-expression of the NRP1/PlexA1 complex and Sema3A in the same neuron, has been formulated based on studies of ephrin. It has been shown that this chemorepulsive guidance molecule can functionally modulate its receptor when co-expressed in the same neuron.135 If the same is true for Sema3A signaling, regenerating peripheral axons, that have downregulated their Sema3A expression, would be more sensitive for Sema3A released from other sources. In this context it is interesting that upon injury, Sema3A expression is induced in terminal Schwann cells at endplates in the target muscle, suggesting a role for Sema3A in post-lesion stabilization of the newly formed neuromuscular junction19,20 (Figure 5E).

Peripheral nerve injury is not only followed by axon regeneration of the peripheral stump, but also by reorganization of sensory terminal arbors in the dorsal and ventral spinal cord. Among the connections that undergo reorganization are the proprioceptive fibers that synapse on the motor neuron cell bodies and dendrites.136 Downregulation of Sema3A in motor neurons after nerve injury might contribute to or might even be a prerequisite for altering these and other spinal connections. A subpopulation of sensory neurons in the DRG upregulates or continues to expresses NRP1 following peripheral nerve crush rendering their central projections in the dorsal and ventral spinal cord potentially sensitive for Sema3A.132 Several studies have shown that both developing and adult sensory fibers are repelled by Sema3A and Sema3E in vitro.7,79,137-140 Functional evidence that adult neurons in vivo can respond to semaphorins comes from studies in the rabbit cornea. Tanelian et al8 showed that ectopic expression of Sema3A causes retraction of established, and repulsion of regenerating, Ad and C sensory fibers in the adult cornea.

Conclusions

In the injured peripheral nervous system the regulation of semaphorin and neuropilin appears to be consistent with successful regeneration and target re-innervation (Figure 6). Regenerating NRP1/Plex-A1-positive spinal motor neurons do not encounter semaphorins at the lesion site, and even down-regulate their own Sema3A expression. Whether downregulation of Sema3A by the motor neuron itself prevents inhibition of its own axonal growth and/or has a function during the reorganization of central DRG projections in the ventral and dorsal spinal cord, needs further study. To date, sensory fibers in the rabbit cornea are the only peripheral adult axons proven to be responsive towards ectopically expressed Sema3A.8

Figure 6. Central versus peripheral nervous regeneration: proposed role of semaphorins and neuropilins.

Figure 6

Central versus peripheral nervous regeneration: proposed role of semaphorins and neuropilins. Peripheral nerve injury induces the expression of a neurite outgrowth supporting gene program (e.g., the upregulation of growth-associated proteins, GAPs) by (more...)

The appearance of class 3 semaphorins at the adult CNS lesion site correlates with the incapability of adult NRP/Plex positive fibers to penetrate the neural scar. To this date there is no functional evidence elucidating the role of class 3 semaphorins and their receptors in the adult mammalian central nervous system. Future studies should clarify if and how neuropilin/ plexin/semaphorin signaling interferes with CNS regeneration and contributes to various aspects of neural scar formation, including migration and angiogenesis. Inactivation of specific ligands and/or receptors using function blocking antibodies, together with genetic manipulation will provide insights in these distinct roles. Recent studies have shown the possibility to convert the response of growth cones from repulsion to attraction by manipulating the intracellular signaling pathways.141 This might be a powerful approach to circumvent the inhibitory nature of neural scars and would help to improve the regenerative capacity of the adult mammalian central nervous system.38

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