Neurotrophin-4/5 is implicated in the enhancement of axon regeneration produced by treadmill training following peripheral nerve injury

The role of neurotrophin-4/5 (NT-4/5) in the enhancement of axon regeneration in peripheral nerves produced by treadmill training was studied in mice. Common fibular nerves of animals of the H strain of thy-1-YFP mice, in which a subset of axons in peripheral nerves is marked by the presence of yellow fluorescent protein, were cut and surgically repaired using nerve grafts from non-fluorescent mice. Lengths of profiles of fluorescent regenerating axons were measured using optical sections made through whole mounts of harvested nerves. Measurements from mice that had undergone 1 h of daily treadmill training at modest speed (10 m/min) were compared with those of untrained (control) mice. Modest treadmill training resulted in fluorescent axon profiles that were nearly twice as long as controls at 1, 2 and 4 week survival times. Similar enhanced regeneration was found when cut nerves of wild type mice were repaired with grafts from NT-4/5 knockout mice or grafts made acellular by repeated freezing/thawing. No enhancement was produced by treadmill training in NT-4/5 knockout mice, irrespective of the nature of the graft used to repair the cut nerve. Much as had been observed previously for the effects of brief electrical stimulation, the effects of treadmill training on axon regeneration in cut peripheral nerves are independent of changes produced in the distal segment of the cut nerve and depend on the promotion of axon regeneration by changes in NT-4/5 expression by cells in the proximal nerve segment.     

Optic axons regenerate into sciatic nerve isografts only in the presence of Schwann cells

Optic axons regenerate into normal but not acellular peripheral nerve (PN) grafts. The first axons penetrate the PN graft before 5 days and grow inside the basal lamina tubes amongst the Schwann cells. By 30 days, 4% of the surviving retinal ganglion cells (RGC) regenerate axons for at least 10 mm into the PN graft. Laminin rich basal lamina tubes persist in the acellular PN transplants but only a few axons penetrate the most proximal parts of the tubes by 5 days and none grow farther into the graft by 30 days. RGC counts demonstrate that 34% of the normal RGC population survive 30 days after anastomosing a normal PN to the transected optic nerve. After anastomosing acellular PN grafts, 25% of RGCs survive compared with 10% after optic nerve section. These findings demonstrate that laminin does not promote regeneration of axons and that Schwann cells play the primary role of offering trophic support and even a substrate for growth. RGC survival is also enhanced by PN grafts even when Schwann cells are absent. This latter result suggests that RGC survival is promoted by a trophic substance released from axons and/or Schwann cells in the PN grafts which survives the thawing/freezing procedure (used to kill the Schwann cells) and is active in the grafts in the immediate post operative period.     

Axon regeneration in peripheral nerves is enhanced by proteoglycan degradation

Regeneration of axons in the peripheral nervous system is enhanced by the removal of glycosaminoglycan side chains (GAGs) of chondroitin sulfate proteoglycans. However, some axons regenerate poorly despite such treatment, suggesting the existence of additional inhibitors. We compared the effects of enzymatic removal of GAGs from chondroitin sulfate proteoglycans versus two other proteoglycan species, heparan sulfate and keratan sulfate proteoglycans, on the regeneration of peripheral axons. Common fibular (CF) nerves of thy-1-YFP-H mice were cut and repaired using short segments of CF nerves harvested from wild-type littermates and pre-treated with a GAG-degrading enzyme for 1 h prior to nerve repair. Axonal regeneration was assayed by measuring the lengths of profiles of YFP+ axons in optical sections of the grafted nerves 1 week later. Except for grafts treated with keratanase, more and longer axon profiles were encountered in enzyme-treated grafts than in control grafts. Heparinase III treatments induced the greatest number of axons to enter into the graft. The proportions of axon profiles longer than 1000 microm were greater in grafts treated with chondroitinase ABC or heparinase I, but not with either keratanase or heparinase III. More regenerative sprouts were observed after treatment with heparinase I than any other enzymes. Treatment with a mixture of all four enzymes resulted in an enhancement of axon regeneration which was greater than that observed after treatment with any of the enzymes individually. The effects of chondroitinase ABC and heparinase III were correlated with specific GAG degradation. We believe that enzymatic removal of GAGs is especially effective in promoting the ability of regenerating axons to select their pathway in the distal stump (or nerve graft) and, in the case of chondroitinase ABC or heparinase I, it may also promote growth within that pathway.     

Endogenous BDNF is required for myelination and regeneration of injured sciatic nerve in rodents

Following a peripheral nerve injury, brain-derived neurotrophic factor (BDNF) and the p75 neurotrophin receptor are upregulated in Schwann cells of the Wallerian degenerating nerves. However, it is not known whether the endogenous BDNF is critical for the functions of Schwann cells and regeneration of injured nerve. Treatment with BDNF antibody was shown to retard the length of the regenerated nerve from injury site by 24%. Histological and ultrastructural examination showed that the number and density of myelinated axons in the distal side of the lesion in the antibody-treated mice was reduced by 83%. In the BDNF antibody-treated animals, there were only distorted and disorganized myelinated fibres in the injured nerve where abnormal Schwann cells and phagocytes were present. As a result of nerve degeneration in BDNF antibody-treated animals, subcellular organelles, such as mitochondria, disappeared or were disorganized and the laminal layers of the myelin sheath were loosened, separated or collapsed. Our in situ hybridization revealed that BDNF mRNA was expressed in Schwann cells in the distal segment of lesioned nerve and in the denervated muscle fibres. These results indicate that Schwann cells and muscle fibres may contribute to the sources of BDNF during regeneration and that the deprivation of endogenous BDNF results in an impairment in regeneration and myelination of regenerating axons. It is concluded that endogenous BDNF is required for peripheral nerve regeneration and remyelination after injury.     

PERIPHERAL NERVE REGENERATION THROUGH GRAFTS OF LIVING AND FREEZE-DRIED CNS TISSUE

The ability of peripheral nerve fibres to regenerate through the central nervous system (CNS) extracellular matrix in the presence of CNS myelin debris was examined using living and freeze-dried optic nerve grafts. The grafts were placed end-to-end with the proximal stumps of severed common peroneal nerves of inbred mice. Within a 4 week period, regenerating peripheral nervous system fibres were found in only two of 14 living grafts. However axons always grew into freeze-dried grafts within one week, despite the presence of CNS myelin debris. The regenerating axons in freeze-dried grafts were accompanied by Schwann cells and were initially found associated with the inner aspect of the glial basal lamina. Although the extracellular matrix of the freeze-dried CNS tissue was subsequently reorganized by invading cells, it seems likely that neither the nature of the CNS extracellular matrix nor the presence of CNS myelin debris had a major inhibitory influence on peripheral nerve regeneration. It is suggested that the presence of living astrocytes covered by a basal lamina at the proximal end of the living optic nerve grafts may inhibit their penetration by regenerating axons.     

Optic nerve regeneration within artificial Schwann cell graft in the adult rat

We investigate whether an artificial graft made by cultured Schwann cell, extracellular matrix (ECM) and trophic factors can provide the environment for the regeneration of retinal ganglion cell (RGC) axons in adult rats. Six kinds of artificial grafts were used: ECM (control); ECM and Schwann cells; ECM, Schwann cells and either nerve growth factor, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4); ECM, Schwann cells, BDNF and NT-4, combined with intravitreal injection of BDNF. The grafts were transplanted onto the transected optic nerve. RGC regeneration was evaluated by dil retrograde labeling, immunohistochemistry, and electron microscopy at 3 weeks post-operation. The degree of dil labeled RGC was approximately 2% for ECM alone, and 10% for ECM and Schwann cells (p < 0.01). The labeling increased to approximately 20% by administration of neurotrophins. The addition of intravitreous BDNF injection resulted in highest labeling percentage of 30%. Immunohistochemical study showed that axons were association with GAP-43 and cell adhesion molecules. Neurotrophin receptors (Trk-A and Trk-B) were detected in nerve fibers both in the retina and in the graft. Remyelination was seen by electron microscopic observation. These results demonstrate that the regeneration of RGC axons is induced with the use of cultured Schwann cells and ECM as promoting factors for regrowth. The degree of regeneration was significantly increased by neurotrophins in the grafts and in the vitreous.     

Further Studies on Motor and Sensory Nerve Regeneration in Mice With Delayed Wallerian Degeneration

The axons of both peripheral and central neurons in C57BL/Wld ^s (C57BL/Ola) mice are unique among mammals in degenerating extremely slowly after axotomy. Motor and sensory axons attempting to regenerate are thus confronted with an intact distal nerve stump rather than axon-and myelin-free Schwann cell-filled endoneurial tubes. Surprisingly, however, motor axons in the sciatic nerve innervating the soleus muscle regenerate rapidly, and there is evidence that they may use Schwann cells associated with unmyelinated fibres as a pathway. If this is so, motor axon regeneration might be impaired in C57BL/Wld ^s mice in the phrenic nerve, which has very few unmyelinated fibres. We found that as long as the myelinated axons in the distal stump of the phrenic nerve remained intact (up to 10 days), regeneration of motor axons did not occur, in spite of vigorous production of sprouts at the crush site. In contrast to motor axons, myelinated sensory axons regenerate very poorly in C57BL/Wld ^s mice, even in the presence of unmyelinated axons. We showed that this was also due to adverse local conditions confronting nerve sprouts, for the dorsal root ganglion cell bodies responded normally to injury with a rapid induction of Jun protein-like immunoreactivity and when the saphenous nerve was forced to degenerate more rapidly by multiple crush lesions sensory axons regrew much more successfully. The findings show that motor and sensory axons in C57BL/Wld ^s mice, although very atypical in the way that they degenerate, are able to regenerate normally but only in an appropriate environment. The results also give support to the view that intact peripheral nerves either fail to encourage or actively inhibit axon growth, and that an unsuitable local environment can prevent regeneration even if the cell body is reacting normally to injury.     

Chemical communication between regenerating motor axons and Schwann cells in the growth pathway

There are receptors on denervated Schwann cells that may respond to the neurotransmitters that are released from growth cones of regenerating motor axons. In order to ascertain whether the interaction of the transmitters and their receptors plays a role during axon regeneration, we investigated whether pharmacological block of the interaction would reduce the number of motoneurons that regenerate their axons after nerve section and surgical repair. Peripheral nerves in the hindlimbs of rats and mice were cut and repaired, and various drugs were applied to the peripheral nerve stump either directly or via mini-osmotic pumps over a 2–4-week period to block the binding of acetylcholine to nicotinic and muscarinic acetylcholine receptors (AChRs: α-bungarotoxin, tubocurarine, atropine and, gallamine) and binding of ATP to P2Y receptors (suramin). In rats, the nicotinic AChR antagonistic drugs and suramin reduced the number of motoneurons that regenerated their axons through the distal nerve stump. In mice, suramin significantly reduced the upregulation of the carbohydrate HNK-1 on the Schwann cells in the distal nerve stump that normally occurs during motor axon regeneration. These data indicate that chemical communication between regenerating axons and Schwann cells during axon regeneration via released neurotransmitters and their receptors may play an important role in axon regeneration.     

AN ULTRASTRUCTURAL STUDY OF THE EARLY STAGES OF AXONAL REGENERATION THROUGH RAT NERVE GRAFTS

Segments of rat sciatic nerve 5 mm long were removed and either maintained alive in tissue culture medium or killed by freeze-drying. Twenty-four h later the nerve segments were replaced as autografts. Animals were killed 3-14 days after grafting. Grafts of cultured nerves (C-grafts) always contained many living cells. Grafts of freeze-dried nerves (FD-grafts) contained few living cells at 3 days, but were repopulated by 7 days. A few regenerating axons were identified in the most proximal parts of 3 day C-grafts and by 14 days many myelinated axons extended to the distal ends. Axons were absent from 3 and 7 day FD-grafts, but by 14 days some non-myelinated axons extended to the distal end of such grafts. Regenerating axons were always associated with Schwann cells. Small perineurial compartments were formed at the junctional zones of all grafts and throughout the FD-grafts. Revascularization of the FD-grafts was delayed when compared to that in C-grafts. Fenestrated capillaries were observed in both types of graft. These experiments demonstrate that axons regenerate through FD-grafts that have been repopulated by cells and the grafts probably lack the normal perineurial and blood/nerve diffusion barriers. The significance of these results is discussed in relation to the requirements for successful axonal regeneration.     

Comparison of different biogenic matrices seeded with cultured Schwann cells for bridging peripheral nerve defects

Tissue-engineering as laboratory based alternative to human autografts and allografts provides "custom made organs" cultured from patient's material. To overcome the limited donor nerve availability different biologic nerve grafts were engineered in a rat sciatic nerve model: cultured isogenic Schwann cells were implanted into acellular autologous matrices: veins, muscles, nerves, and epineurium tubes. Autologous nerve grafts, and the respective biogenic material without Schwann cells served as control. After 6 weeks regeneration was assessed clinically, histologically and morphometrically. The PCR analysis showed that the implanted Schwann cells remain within all the grafts. A good regeneration was noted in the muscle-Schwann cell-group, while regeneration quality in the other groups (with or without Schwann cells) was impaired. The muscle-Schwann cell graft showed a systematic and organized regeneration including a proper orientation of regenerated fibers. All venous and epineurium grafts had a more disorganized regeneration. Seemingly, the lack of endoneural tube like structures in vein grafts lead to impaired regeneration. And, apparently, the beneficial effects of implanted Schwann cells into a large luminal structure can only be demonstrated to a limited extent if endoneural like structures are lacking. A tube offers less area for Schwann cell adhesion and it is more likely to collapse. This underlines the role of the basal lamina, or at least an inner structure acting as scaffold in axonal regeneration. Although the conventional nerve graft remains the gold standard, the implantation of Schwann cells into an acellular muscle provides a biogenic graft with basal lamina tubes as pathway for regenerating axons and the positive effects of Schwann cells producing neurotrophic and neurotropic factors, and thus, supporting axonal regeneration.     

Molecular basis of interactions between regenerating adult rat thalamic axons and Schwann cells in peripheral nerve grafts II. Tenascin-C

Tenascin-C is a developmentally regulated extracellular matrix component. There is evidence that it may be involved in axon growth and regeneration in peripheral nerves. We have used in situ hybridization and immunocytochemistry to investigate the association of tenascin-C with central nervous system axons regenerating through a peripheral nerve autograft inserted into the thalamus of adult rats. Between 3 days and 4 weeks after implantation, tenascin-C immunoreactivity was increased in the grafts, first at the graft/brain interface, then in the endoneurium of the graft, and finally within the Schwann cell columns of the graft. By electron microscopy, reaction product was present around collagen fibrils and basal laminae in the endoneurium, but the heaviest deposits were found at the surface of regenerating thalamic axons within Schwann cell columns. Schwann cell surfaces were not associated with tenascin-C reaction product except where they faced the tenascin-rich basal lamina or were immediately opposite axons surrounded by tenascin-C. By 8 weeks after graft implantation tenascin-C in the endoneurium and around axons of the graft was decreased. In the brain parenchyma aroundthe proximal part of the graft, axonal sprouts associated with tenascin-C could not be identified earlier than 2 weeks after grafting and were sparse at this stage. Larger numbers of such axons were present at 8–13 weeks after grafting and were located predominantly where the glia limitans between brain and graft appeared to be incomplete, suggesting that the tenascin-C may have penetrated the brain parenchyma from the graft. By in situ hybridization, cells expressing tenascin-C mRNA (probably Schwann cells) appeared first at the brain/graft interface 3 days after grafting and thereafter were mainly located within the grafts. Lightly labelled cells containing tenascin-C mRNA (probably glial cells) were scattered in the thalamic parenchyma both ipsilateral and contralateral to the graft and a few heavily labelled cells were located very close to the tip of the graft. These results show that regenerating adult thalamic axons, unlike regenerating peripheral axons, become intimately associated with peripheral nerve graft-derived tenascin-C, suggesting that they express a tenascin-C receptor, as many neurons do during development, and that tenascin-C derived from Schwann cells may play a role in the regenerative growth of such axons through the grafts. © 1995 Wiley-Liss, Inc.     

Influence of autograft size on peripheral nerve regeneration in cats

A combination of electrophysiological and histological techniques has been used to study the extent to which the size of an autograft affects myelinated axon regeneration in damaged cat peripheral nerves. The length of the graft and the match between the number of axons and Schwann cell basement membrane tubes in the graft and the repaired nerve were investigated. No difference was found in the success of regeneration through 10, 20 and 30 mm autografts. Changing the number of Schwann cell tubes available to regenerating myelinated axons also had no detectable effect on the success of regeneration.     

Glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor sustain the axonal regeneration of chronically axotomized motoneurons in vivo

In contrast to injuries in the central nervous system, injured peripheral neurons will regenerate their axons. However, axotomized motoneurons progressively lose their ability to regenerate their axons, following peripheral nerve injury often resulting in very poor recovery of motor function. A decline in neurotrophic support may be partially responsible for this effect. The initial upregulation of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) by Schwann cells of the distal nerve stump after nerve injury has led to the speculation that they are important for motor axonal regeneration. However, few experiments directly measure the effects of exogenous BDNF or GDNF on motor axonal regeneration. This study provided the first direct and quantitative evidence that long-term continuous treatment with exogenous GDNF significantly increased the number of motoneurons which regenerate their axons, completely reversing the negative effects of chronic axotomy. The beneficial effect of GDNF was not dose-dependent. A combination of exogenous GDNF and BDNF on motor axonal regeneration was significantly greater than either factor alone, and this effect was most pronounced following long-term continuous treatment. The ability of GDNF, either alone or in combination with BDNF, to increase the number of motoneurons that regenerated their axons correlated well with an increase in axon sprouting within the distal nerve stump. Thus long-term continuous treatment with neurotrophic factors, such as GDNF and BDNF, can be used as a viable treatment to sustain motor axon regeneration.     

Comparison of different biogenic matrices seeded with cultured Schwann cells for bridging peripheral nerve defects

Abstract

Tissue-engineering as laboratory based alternative to human autografts and allografts provides "custom made organs" cultured from patient's material. To overcome the limited donor nerve availability different biologic nerve grafts were engineered in a rat sciatic nerve model: cultured isogenic Schwann cells were implanted into acellular autologous matrices: veins, muscles, nerves, and epineurium tubes. Autologous nerve grafts, and the respective biogenic material without Schwann cells served as control. After 6 weeks regeneration was assessed clinically, histologically and morphometrically. The PCR analysis showed that the implanted Schwann cells remain within all the grafts. A good regeneration was noted in the muscle-Schwann cell-group, while regeneration quality in the other groups (with or without Schwann cells) was impaired. The muscle-Schwann cell graft showed a systematic and organized regeneration including a proper orientation of regenerated fibers. All venous and epineurium grafts had a more disorganized regeneration. Seemingly, the lack of endoneural tube like structures in vein grafts lead to impaired regeneration. And, apparently,the beneficial effects of implanted Schwann cells into a large luminal structure can only be demonstrated to a limited extent if endoneural like structures are lacking. A tube offers less area for Schwann cell adhesion and it is more likely to collapse. This underlines the role of the basal lamina, or at least an inner structure acting as scaffold in axonal regeneration. Although the conventional nerve graft remains the gold standard, the implantation of Schwann cells into an acellular muscle provides a biogenic graft with basal lamina tubes as pathway for regenerating axons and the positive effects of Schwann cells producing neurotrophic and neurotropic factors, and thus, supporting axonal regeneration.     

The role of Schwann cells and basal lamina tubes in the regeneration of axons through long lengths of freeze-killed nerve grafts

The ability of long acellular nerve grafts to support axonal regeneration was examined using inbred rats. Grafts (40 mm long) of tibial/plantar nerves were used either as live grafts or after freeze-drying to render the grafts acellular. The grafts were sutured to the proximal stump of severed tibial nerves in host animals which were then killed 1-12 weeks later. Axons rapidly regenerated through the living grafts but only extended 10-20 mm into the acellular grafts. This distance was achieved by 6 weeks and thereafter no significant further axonal extension occurred in the acellular grafts. A few naked axons lacking Schwann cell contact were identified in all acellular grafts, but became more numerous near the distal extent of axonal penetration into 6-12 week grafts. These axons contained large numbers of neurofilaments. When the distal 20 mm of 6 week acellular grafts (segments into which axons had not penetrated) were sutured to freshly severed tibial nerves, axons grew readily into the grafted tissue to a maximum distance of 9 mm. It is therefore likely that the limits to axonal regeneration through initially acellular grafts were set by factors intrinsic to the severed nerve. It is suggested that the limited migratory powers of Schwann cells may be one such factor. The concept that basal lamina tubes are not essential for axonal regeneration but may act as low resistance pathways for both axonal elongation and Schwann cell migration is discussed.     

A double-transgenic mouse used to track migrating Schwann cells and regenerating axons following engraftment of injured nerves

We propose that double-transgenic thy1-CFP(23)/S100-GFP mice whose Schwann cells constitutively express green fluorescent protein (GFP) and axons express cyan fluorescent protein (CFP) can be used to serially evaluate the temporal relationship between nerve regeneration and Schwann cell migration through acellular nerve grafts. Thy1-CFP(23)/S100-GFP and S100-GFP mice received non-fluorescing cold preserved nerve allografts from immunologically disparate donors. In vivo fluorescent imaging of these grafts was then performed at multiple points. The transected sciatic nerve was reconstructed with a 1-cm nerve allograft harvested from a Balb-C mouse and acellularized via 7 weeks of cold preservation prior to transplantation. The presence of regenerated axons and migrating Schwann cells was confirmed with confocal and electron microscopy on fixed tissue. Schwann cells migrated into the acellular graft (163+/-15 intensity units) from both proximal and distal stumps, and bridged the whole graft within 10 days (388+/-107 intensity units in the central 4-6 mm segment). Nerve regeneration lagged behind Schwann cell migration with 5 or 6 axons imaged traversing the proximal 4 mm of the graft under confocal microcopy within 10 days, and up to 21 labeled axons crossing the distal coaptation site by 15 days. Corroborative electron and light microscopy 5 mm into the graft demonstrated relatively narrow diameter myelinated (431+/-31) and unmyelinated (64+/-9) axons by 28 but not 10 days. Live imaging of the double-transgenic thy1-CFP(23)/S100-GFP murine line enabled serial assessment of Schwann cell-axonal relationships in traumatic nerve injuries reconstructed with acellular nerve allografts.     

Neurotrophin-4/5 is required for the early growth of regenerating axons in peripheral nerves

The requirement of the trkB ligand, neurotrophin-4/5 (NT-4/5), for the growth of regenerating axons in the peripheral nervous system (PNS) is not well established. We studied regenerating axon growth in transected peripheral nerves of thy-1-YFP-H mice that had been repaired using allografts obtained from brain-derived neurotrophic factor (BDNF) or NT-4/5 knockout mice. Lengths of profiles of YFP+ axons measured in these grafts were compared with those measured in grafts obtained from wild-type donors. When compared with axon profiles measured in grafts from wild-type donors, axon profile lengths measured in grafts from homozygous (NT-4/5(-/-)) or heterozygous (NT-4/5(+/-)) mice were significantly shorter. In contrast, the lengths of axon profiles measured in grafts from BDNF(+/-) mice were not significantly different from those measured in grafts from wild-type mice. A reduced amount of BDNF, but not NT-4/5, is sufficient to promote the elongation of regenerating axons in the PNS. When grafts from wild-type or NT-4/5(-/-) mice were treated acutely at the time of surgical repair either with exogenous BDNF or NT-4/5, the lengths of axon profiles measured in the grafts were significantly longer than those measured in grafts from untreated wild-type mice. These findings are consistent with a requirement for NT-4/5 from within the pathway used by regenerating axons for the successful growth of those axons in peripheral nerves.     

Retinal ganglion cell axons regenerate in the presence of intact sensory fibres

A novel allograft paradigm was used to test whether adult mammalian central axons regenerate within a peripheral nerve environment containing intact sensory axons. Retinal ganglion cell axon regeneration was compared following anastomosis of dorsal root ganglia grafts or conventional peripheral nerve grafts to the adult rat optic nerve. Dorsal root ganglia grafts comprised intact sensory and degenerate motor axons, whereas conventional grafts comprised both degenerating sensory and motor axons. Retinal ganglion cell axons were traced after 2 months. Dorsal root ganglia survived with their axons persisting throughout the graft. Comparable numbers of retinal ganglion cells regenerated axons into both dorsal root ganglia (1053+/-223) and conventional grafts (1323+/-881; P>0.05). The results indicate that an intact sensory environment supports central axon regeneration.     

Receptor protein tyrosine phosphatase sigma inhibits axon regrowth in the adult injured CNS

Recently, receptor protein tyrosine phosphatase-sigma (RPTPsigma) has been shown to inhibit axon regeneration in injured peripheral nerves. Unlike the peripheral nervous system (PNS), central nervous system (CNS) neurons fail to regenerate their axons after injury or in disease. In order to assess the role of RPTPsigma in CNS regeneration, we used the retinocollicular system of adult mice lacking RPTPsigma to evaluate retinal ganglion cell (RGC) axon regrowth after optic nerve lesion. Quantitative analysis demonstrated a significant increase in the number of RGC axons that crossed the glial scar and extended distally in optic nerves from RPTPsigma (-/-) mice compared to wild-type littermate controls. Although we found that RPTPsigma is expressed by adult RGCs in wild-type mice, the retinas and optic nerves of adult RPTPsigma (-/-) mice showed no histological defects. Furthermore, the time-course of RGC death after nerve lesion was not different between knockout and wild-type animals. Thus, enhanced axon regrowth in the absence of RPTPsigma could not be attributed to developmental defects or increased neuronal survival. Finally, we show constitutively elevated activity of mitogen-activated protein kinase (MAPK) and Akt kinase in adult RPTPsigma (-/-) mice retinas, suggesting that these signaling pathways may contribute to promoting RGC axon regrowth following traumatic nerve injury. Our results support a model in which RPTPsigma inhibits axon regeneration in the adult injured CNS.