Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “axon regeneration”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2006

The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration.

Axon regeneration is substantially regulated by gene expression and cytoskeleton remodeling. Here we show that the tumor suppressor protein p53 is required for neurite outgrowth in cultured cells including primary neurons as well as for axonal regeneration in mice. These effects are mediated by two newly identified p53 transcriptional targets, the actin-binding protein Coronin 1b and the GTPase Rab13, both of which associate with the cytoskeleton and regulate neurite outgrowth. We also demonstrate that acetylation of lysine 320 (K320) of p53 is specifically involved in the promotion of neurite outgrowth and in the regulation of the expression of Coronin 1b and Rab13. Thus, in addition to its recognized role in neuronal apoptosis, surprisingly, p53 is required for neurite outgrowth and axonal regeneration, likely through a different post-translational pathway. These observations may suggest a novel therapeutic target for promoting regenerative responses following peripheral or central nervous system injuries.

Acetylation↗
PubMed1997

Determinants of axonal regeneration.

Axons often regrow to their targets and lost functions may be restored after an injury in the peripheral nervous system. In contrast, axonal regeneration is generally very limited after injuries in the central nervous system, and functional impairment is usually permanent. The regenerative capacity depends on intrinsic neuronal factors as well as the interaction of neurons with other cells. Glial cells may, in different situations, either support or inhibit axonal growth. This review discusses the molecular mechanisms that are involved in promoting and inhibiting axonal regeneration in the nervous system after injuries.

Animals↗
PubMed2004

Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration.

Axon regeneration is arrested in the injured central nervous system (CNS) by axon growth-inhibitory ligands expressed in oligodendrocytes/myelin, NG2-glia, and reactive astrocytes in the lesion and degenerating tracts, and by fibroblasts in scar tissue. Growth cone receptors (Rc) bind inhibitory ligands, activating a Rho-family GTPase intracellular signaling pathway that disrupts the actin cytoskeleton inducing growth cone collapse/repulsion. The known inhibitory ligands include the chondroitin sulfate proteoglycans (CSPG) Neurocan, Brevican, Phosphacan, Tenascin, and NG2, as either membrane-bound or secreted molecules; Ephrins expressed on astrocyte/fibroblast membranes; the myelin/oligodendrocyte-derived growth inhibitors Nogo, MAG, and OMgp; and membrane-bound semaphorins (Sema) produced by meningeal fibroblasts invading the scar. No definitive CSPG Rc have been identified, although intracellular signaling through the Rho family of G-proteins is probably common to all the inhibitory ligands. Ephrins bind to signalling Ephs. The ligand-binding Rc for all the myelin inhibitors is NgR and requires p75(NTR) for transmembrane signaling. The neuropilin (NP)/plexin (Plex) Rc complex binds Sema. Strategies for promoting axon growth after CNS injury are thwarted by the plethora of inhibitory ligands and the ligand promiscuity of some of their Rc. There is also paradoxical reciprocal expression of many of the inhibitory ligands/Rc in normal and damaged neurons, and NgR expression is restricted to a limited number of neuronal populations. All these factors, together with an incomplete understanding of the normal functions of many of these molecules in the intact CNS, presently confound interpretive acumen in regenerative studies.

Animals↗
PubMed1996

Reductions in motoneuronal neurofilament synthesis by successive axotomies: a possible explanation for the conditioning lesion effect on axon regeneration.

Axons regenerate more rapidly after a test lesion if they received a conditioning lesion. Previous work suggests that the cell body reaction to injury is responsible for this conditioning lesion effect. Here we examined the effects of the second, test lesion on the expression of the major cytoskeletal proteins, tubulin, actin, and neurofilament proteins. Using 2D-SDS-PAGE to separate these cytoskeletal proteins synthesized in the facial nucleus, along with in situ hybridization and RNA blotting to measure corresponding mRNA levels, we found that previous conditioning had little effect on actin or tubulin responses to a test lesion, but resulted in further decrease in neurofilament synthesis. Immunocytochemistry and electron microscopy revealed a greater loss of neurofilaments from the proximal conditioned axons, and axonal shrinkage. We suggest that the reduction in neurofilaments in the proximal axons of conditioned neurons reduces interference with tubulin transport. This may allow more tubulin to be transported more rapidly into the growing axon, to support the faster elongation rate of conditioned axons following a test lesion.

Animals↗
PubMed1996

Axonal regeneration.

Axons damaged in a peripheral nerve are often able to regenerate from the site of injury along the degenerate distal segment of the nerve to reform functional synapses. Schwann cells play a central role in this process. However, in the adult mammalian central nervous system, from which Schwann cells are absent, axonal regeneration does not progress to allow functional recovery. This is due to inhibitors of axonal growth produced by both oligodendrocytes and astrocytes and also to the decreased ability of adult neurons to extend axons during regeneration compared to embryonic neurons during development. However once provided with a substrate conducive to axonal growth, such as a peripheral nerve graft, many central neurons are able to regenerate axons over long distances. Over the past year this response has been utilised in experimental models to produce a degree of behavioural recovery.

Animals↗
PubMed1998

Selective inhibition of early axonal regeneration by myelin-associated glycoprotein.

When the distal stump of a transected peripheral nerve is brought into the vicinity of the proximal nerve stump, the regenerating axons advance toward it across the gap. Similar results are obtained when a predegenerated nerve segment is used. However, when a nerve segment subjected to proximal axotomy 7 days earlier (7-day nerve segment) was placed close to the proximal end of a freshly cut nerve at a distance of less than 1.5 mm, there were neither regenerating axons nor sprouts. The same inhibition of axonal regeneration was also exhibited when a nerve segment subjected to axotomy 9 to 14 days earlier was used. To examine the inhibitory effect of the nerve segments on established regenerating axons, we positioned a 7-day nerve segment in close apposition to a proximal nerve end at 2 or 3 days after transection. The growth of the 3-day-old regenerating axons, already ensheathed by Schwann cells, was not disturbed, but the 2-day-old regenerating axons, consisting of naked axons, were eliminated by the 7-day nerve segment. It is assumed that the findings reflect a mechanism serving to eliminate abundant sprouts and immature axons, probably conferring optimum regeneration and maturation of outgrowing pioneer axons. The inhibitory effect on abundant sprouts and immature axons was completely blocked by local application of antibodies to myelin-associated glycoprotein (MAG). The MAG-containing cells appeared at 6 to 12 days after axotomy.

Animals↗
PubMed2006

Regenerating axons emerge far proximal to the coaptation site in end-to-side nerve coaptation without a perineurial window using a T-shaped chamber.

BACKGROUND: Considerable controversy exists concerning the mechanism of axonal regeneration in end-to-side neurorrhaphy. The authors studied the mode of axonal regeneration in end-to-side neurorrhaphy without a perineurial window using a rat sciatic nerve model. METHODS: Twenty-seven rats were used. A 10-mm segment of peroneal nerve was harvested and coapted to the ipsilateral tibial nerve in end-to-side fashion using a T-shaped silicone chamber to minimize the tibial nerve damaged by surgery. To explain the role of nerve damage on axonal regeneration in end-to-side neurorrhaphy, we also used an isogenic nerve transplantation model in which the peroneal nerve remained intact. The mode of axonal regeneration was studied with electron microscopy, morphometric analysis, immunofluorescence, and immunohistochemistry. RESULTS: Both morphometric analysis and immunolabeling of neurofilaments demonstrated that regenerating axons emerge at sites far proximal to the coaptation site, travel within the tibial nerve, traverse the perineurium circumferentially around the coaptation site, and then invade into the peroneal nerve. Electron microscopy and a double-labeled immunofluorescence study with antibodies against neurofilament and tenascin-C confirmed large-scale axonal penetration into the perineurium around the coaptation site. Immunofluorescence with antibody against NG2, a marker of axonal regeneration, prevented the possibility of collateral sprouting at the coaptation site. In addition, an end-to-side neurorrhaphy model with an isogenic peroneal nerve clearly demonstrated that nerve damage is a prerequisite for axonal regeneration through end-to-side neurorrhaphy. CONCLUSIONS: The authors could not locate the site of axonal sprouting in end-to-side neurorrhaphy without a perineurial window; however, this study cast doubts on current hypothesis on the mode of axonal regeneration in end-to-side neurorrhaphy.

Animals↗
PubMed2006

Changes within maturing neurons limit axonal regeneration in the developing spinal cord.

Embryonic birds and mammals display a remarkable ability to regenerate axons after spinal injury, but then lose this ability during a discrete developmental transition. To explain this transition, previous research has emphasized the emergence of myelin and other inhibitory factors in the environment of the spinal cord. However, research in other CNS tracts suggests an important role for neuron-intrinsic limitations to axon regeneration. Here we re-examine this issue quantitatively in the hindbrain-spinal projection of the embryonic chick. Using heterochronic cocultures we show that maturation of the spinal cord environment causes a 55% reduction in axon regeneration, while maturation of hindbrain neurons causes a 90% reduction. We further show that young neurons transplanted in vivo into older spinal cord can regenerate axons into myelinated white matter, while older axons regenerate poorly and have reduced growth cone motility on a variety of growth-permissive ligands in vitro, including laminin, L1, and N-cadherin. Finally, we use video analysis of living growth cones to directly document an age-dependent decline in the motility of brainstem axons. These data show that developmental changes in both the spinal cord environment and in brainstem neurons can reduce regeneration, but that the effect of the environment is only partial, while changes in neurons by themselves cause a nearly complete reduction in regeneration. We conclude that maturational events within neurons are a primary cause for the failure of axon regeneration in the spinal cord.

Aging↗
PubMed2000

Axonal regeneration from CNS neurons in the cerebellum and brainstem of adult rats: correlation with the patterns of expression and distribution of messenger RNAs for L1, CHL1, c-jun and growth-associated protein-43.

Some neurons in the brain and spinal cord will regenerate axons into a living peripheral nerve graft inserted at the site of injury, others will not. We have examined the patterns of expression of four molecules thought to be involved in developmental and regenerative axonal growth, in the cerebellum and brainstem of adult rats, following the implantation into the cerebellum of peripheral nerve grafts. We also determined how the expression patterns observed correlate with the abilities of neurons in these regions to regenerate axons. Three days to 16 weeks after insertion of living tibial nerve autografts, neurons which had regenerated axons into the graft were retrogradely labelled from the distal extremity of the graft with cholera toxin conjugated to horseradish peroxidase, and sections through the cerebellum and brainstem were processed for visualization of transported tracer and/or hybridized with riboprobes to detect messenger RNAs for the cell recognition molecules L1 and CHL1 (close homologue of L1), growth-associated protein-43 and the cellular oncogene c-jun. Retrogradely labelled neurons were present in cerebellar deep nuclei close to the graft and in brainstem nuclei known to project to the cerebellum. Neurons in these same nuclei were found to have up-regulated expression of all four messenger RNAs. Individual retrogradely labelled neurons also expressed high levels of L1, CHL1, c-jun or growth-associated protein-43 messenger RNAs (and vice versa), and every messenger RNA investigated was co-localized with at least one other messenger RNA. Purkinje cells did not regenerate axons into the graft or up-regulate L1, CHL1 or growth-associated protein-43 messenger RNAs, but there was increased expression of c-jun messenger RNA in some Purkinje cells close to the graft. Freeze-killed grafts produced no retrograde labelling of neurons, and resulted in only transient and low levels of up-regulation of the tested molecules, mainly L1 and CHL1. These findings show that cerebellar deep nucleus neurons and precerebellar brainstem neurons, but not Purkinje cells, have a high propensity for axon regeneration, and that axonal regeneration by these neurons is accompanied by increased expression of L1, CHL1, c-jun and growth-associated protein-43. Furthermore, although the patterns of expression of the four molecules investigated are not identical in regenerating neuronal populations, it is probable that all four are up-regulated in all neurons whose axons regenerate into the grafts and that their up-regulation may be required for axon regeneration to occur. Finally, because c-jun up-regulation is seen in Purkinje cells close to the graft, unaccompanied by up-regulation of the other molecules investigated, c-jun up-regulation alone cannot be taken to reliably signify a regenerative response to axotomy.

Animals↗
PubMed1992

Progressive morphological abnormalities observed in rat spinal motor neurons at extended intervals after axonal regeneration.

It is generally accepted that mammalian spinal motor neurons return to normal after axotomy if their regenerated axons successfully reinnervate appropriate peripheral targets. However, morphological abnormalities, recently observed in spinal motor neurons examined 1 year after nerve crush injury, raise the possibility that delayed perikaryal changes occur after regeneration is complete. In order to distinguish between chronic and progressive alterations in neurons with long-term regenerated axons, rat spinal motor neurons and dorsal root ganglion cells were examined at 5 and 10 months following unilateral sciatic nerve crush. Neurons with regenerated axons were identified by retrograde labelling with horseradish peroxidase. The structural properties of neurons ipsilateral to nerve injury were compared to those of neurons from the spinal cord and dorsal root ganglia on the contralateral side and from age-matched control rats. At 5 months postcrush, the morphology of motor and sensory neurons ipsilateral to injury was comparable to that of control cells. However, several features of the motor neurons with regenerated axons distinguished them from control motor neurons at 10 months postcrush. Mean perikaryal area of ipsilateral spinal motor neurons was larger than the means for control motor neurons (p less than .001). Ipsilateral spinal motor neurons also appeared clustered within the spinal cord and had thicker dendrites. Dorsal root ganglion cells with regenerated axons were slightly larger than control cells at 10 months postcrush but they exhibited no other morphological changes. The present findings indicate that spinal motor neurons are progressively altered after their regenerated axons have reestablished functional synapses with their peripheral targets.

Animals↗
PubMed1983

Changes in rapid transport of phospholipids in the rat sciatic nerve during axonal regeneration.

Axonal transport of phospholipids in normal and regenerating sciatic nerve of the rat was studied. At various intervals after axotomy of the right sciatic nerve in the midthigh region and subsequent perineurial sutures of the transected fascicles, a mixture of 60 mu Ci [Me-14C]choline and 15 muCi [2-3H]glycerol in the region of the spinal motor neurons of the L5 and L6 segments was injected bilaterally. The amount of radioactive lipid (and in certain cases its distribution in various lipid classes) along the nerve was determined as a function of time. Three days after fascicular suture and 6 h after spinal cord injection of precursors, there was an accumulation of labeled phospholipids and sphingolipids in the transected sciatic nerve in the region immediately proximal to the site of suture. Nine days after, there was a marked increase in the accumulation of radioactivity in the distal segments of the injured nerve, which increased up to 14 days after cutting and disappeared as regeneration proceeded (21-45 days). In all segments of both normal and regenerating nerve fibers, as well as in L5 and L6 spinal cord segments, only phosphatidylcholine and sphingomyelin were labeled with [14C]choline. These results suggest that the regeneration process in a distal segment of a peripheral neuron, following cutting and fascicular repairing by surgical sutures, is sustained in the first 3 weeks by changes in the amount of phospholipids rapidly transported along the axon towards the site of nerve fiber outgrowth.

Animals↗
PubMed2005

Upregulation of activating transcription factor 3 (ATF3) by intrinsic CNS neurons regenerating axons into peripheral nerve grafts.

The expression of the transcription factor ATF3 in the brain was examined by immunohistochemistry during axonal regeneration induced by the implantation of pieces of peripheral nerve into the thalamus of adult rats. After 3 days, ATF3 immunoreactivity was present in many cells within approximately 500 mum of the graft. In addition, ATF3-positive cell nuclei were found in the thalamic reticular nucleus (TRN) and medial geniculate nuclear complex (MGN), from which most regenerating axons originate. CNS cells with ATF3-positive nuclei were predominantly neurons and did not show signs of apoptosis. The number of ATF3-positive cells had declined by 7 days and further by 1 month after grafting when most ATF3-positive cells were found in the TRN and MGN. 14 days or more after grafting, some ATF3-positive nuclei were distorted and may have been apoptotic. In some experiments of 1 month duration, neurons which had regenerated axons to the distal ends of grafts were retrogradely labeled with DiAsp. ATF3-positive neurons in these animals were located in regions of the TRN and MGN containing retrogradely labeled neurons and the great majority were also labeled with DiAsp. SCG10 and c-Jun were found in neurons in the same regions as retrogradely labeled and ATF3-positive cells. Thus, ATF3 is transiently upregulated by injured CNS neurons, but prolonged expression is part of the pattern of gene expression associated with axonal regeneration. The co-expression of ATF3 with c-jun suggests that interactions between these transcription factors may be important for controlling the program of gene expression necessary for regeneration.

Activating Transcription Factor 3↗
PubMedDate not supplied

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.

Animals↗
PubMed1998

Restricted inflammatory reaction in the CNS: a key impediment to axonal regeneration?

Axons in the central nervous system (CNS) of adult mammals do not regenerate after injury. Mammalian CNS differs in this respect from other mammalian tissues, including the peripheral nervous system (PNS), and from the CNS of lower vertebrates. In most parts of the body, including the nervous system, injury triggers an inflammatory reaction involving macrophages. This reaction is needed for tissue healing; when it is delayed or insufficient, healing is incomplete. The CNS, although needing an efficient inflammatory reaction resembling that in the periphery for tissue healing, appears to have lost the ability to supply it. We suggest that restricted CNS recruitment and activation of macrophages are linked to regeneration failure and might reflect the immune privilege that characterizes the mammalian CNS. As macrophages play a critical role in tissue restoration, and because their recruitment and activation are among the most upstream of the events leading to tissue healing, overcoming the deficiencies in these steps might trigger a self-repair processing leading to recovery after CNS injury.

Animals↗
PubMed1997

Axon-regenerating retinal ganglion cells in adult rats synthesize the cell adhesion molecule L1 but not TAG-1 or SC-1.

Retinal ganglion cells (RGCs) in rats regenerate axons in the presence of a PNS nerve graft. To determine if axon-regenerating RGCs synthesize cell adhesion/recognition molecules which they possessed during development, retinae were subjected to in situ hybridization with antisense cRNA probes of L1, TAG-1, and SC-1 (and GAP-43 for comparison). L1 and TAG-1 (and GAP-43) proteins on axons were detected with antibodies. L1, TAG-1, and SC-1 (and Gap-43) mRNAs and L1 and TAG-1 (and Gap-43) proteins were expressed by RGCs in embryonic, postnatal, and adult rats. After optic nerve lesion (ONL), the surviving RGCs between 2 and 28 days after ONL continued to express L1. TAG-1 and SC-1 expression, however is lost. In grafted rats, axon-regenerating RGCs express L1 (together with GAP-43) but neither TAG-1 nor SC-1. Thus, axonal regeneration in grafted rats occurs in the presence of L1 (and GAP-43) but in the absence of TAG-1 and SC-1).

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed1978

Reinnervation of muscle fiber basal lamina after removal of myofibers. Differentiation of regenerating axons at original synaptic sites.

Axons regenerate to reinnervate denervated skeletal muscle fibers precisely at original synaptic sites, and they differentiate into nerve terminals where they contact muscle fibers. The aim of this study was to determine the location of factors that influence the growth and differentiation of the regenerating axons. We damaged and denervated frog muscles, causing myofibers and nerve terminals to degenerate, and then irradiated the animals to prevent regeneration of myofibers. The sheath of basal lamina (BL) that surrounds each myofiber survives these treatments, and original synaptic sites on BL can be recognized by several histological criteria after nerve terminals and muscle cells have been completely removed. Axons regenerate into the region of damage within 2 wk. They contact surviving BL almost exclusively at original synaptic sites; thus, factors that guide the axon's growth are present at synaptic sites and stably maintained outside of the myofiber. Portions of axons that contact the BL acquire active zones and accumulations of synaptic vesicles; thus by morphological criteria they differentiate into nerve terminals even though their postsynaptic targets, the myofibers, are absent. Within the terminals, the synaptic organelles line up opposite periodic specializations in the myofiber's BL, demonstrating that components associated with the BL play a role in organizing the differentiation of the nerve terminal.

Animals↗
PubMed2000

Axonal regeneration, but not myelination, is partially dependent on local cholesterol reutilization in regenerating nerve.

A recycling pathway in peripheral nerve permits cholesterol from degenerating myelin to be salvaged by macrophages and resupplied to myelinating Schwann cells by locally produced lipoproteins. A similar reutilization of cholesterol by regenerating axons has been proposed but not demonstrated. Neurites in culture, however, do take up cholesterol and cholesterol-containing lipoproteins, where these molecules are found to promote neurite extension. To test the requirement for cholesterol reutilization in axon regeneration and myelination, we examined 2 models of blocked intracellular cholesterol transport: 1) bone marrow transplants from Niemann-Pick C mice into wild-type recipient mice, and 2) imipramine treatment. Following nerve crush in these models, we found that unusually large, debris-filled macrophages appeared and persisted for many weeks. A morphometric analysis of regenerating nerves revealed that myelination proceeded at a normal rate (normal g-ratios), but that axon growth was retarded (decreased fiber numbers and diameters) in these animals. Cholesterol synthesis was elevated in these nerves, indicating that Schwann cells compensated for the decreased exogenous supply of cholesterol by up-regulating de novo synthesis to support myelination. These data indicate that Schwann cells are not dependent on cholesterol reutilization to support myelination, but that optimal axonal regeneration is dependent on a local supply of cholesterol.

Adrenergic Uptake Inhibitors↗
PubMed1992

Neurotropic influence of the distal stump of transected peripheral nerve on axonal regeneration: absence of topographic specificity in adult nerve.

Observations have been made on the growth of regenerating axons from transected rat sciatic nerve through Y-shaped silicone tubes. When the distal stump of the nerve was sutured into 1 distal limb of the tube and a fat pad into the other, a clear preference for the axons to regenerate towards the distal stump was found. In other experiments regenerating axons from the peroneal or tibial divisions of the sciatic nerve were given the choice of growing towards either the peroneal or tibial nerves, each being inserted into 1 of the 2 distal limbs of the Y-tube. No significant preference of the proximal stump to regenerate towards its appropriate distal stump was detected. A neurotropic influence of the distal stump on the nerve has therefore been confirmed, but topographic specificity of regeneration at the level of the nerve trunk has not been established.

Animals↗