Key molecules in axon regeneration (original) (raw)
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Axonal Regeneration: Underlying Molecular Mechanisms and Potential Therapeutic Targets
Biomedicines
Axons in the peripheral nervous system have the ability to repair themselves after damage, whereas axons in the central nervous system are unable to do so. A common and important characteristic of damage to the spinal cord, brain, and peripheral nerves is the disruption of axonal regrowth. Interestingly, intrinsic growth factors play a significant role in the axonal regeneration of injured nerves. Various factors such as proteomic profile, microtubule stability, ribosomal location, and signalling pathways mark a line between the central and peripheral axons’ capacity for self-renewal. Unfortunately, glial scar development, myelin-associated inhibitor molecules, lack of neurotrophic factors, and inflammatory reactions are among the factors that restrict axonal regeneration. Molecular pathways such as cAMP, MAPK, JAK/STAT, ATF3/CREB, BMP/SMAD, AKT/mTORC1/p70S6K, PI3K/AKT, GSK-3β/CLASP, BDNF/Trk, Ras/ERK, integrin/FAK, RhoA/ROCK/LIMK, and POSTN/integrin are activated after nerve injury...
Axon Regrowth during Development and Regeneration Following Injury Share Molecular Mechanisms
Current Biology, 2012
Background: The molecular mechanisms that determine axonal growth potential are poorly understood. Intrinsic growth potential decreases with age, and thus one strategy to identify molecular pathways controlling intrinsic growth potential is by studying developing young neurons. The programmed and stereotypic remodeling of Drosophila mushroom body (MB) neurons during metamorphosis offers a unique opportunity to uncover such mechanisms. Despite emerging insights into MB g-neuron axon pruning, nothing is known about the ensuing axon re-extension. Results: Using mosaic loss of function, we found that the nuclear receptor UNF (Nr2e3) is cell autonomously required for the re-extension of MB g-axons following pruning, but not for the initial growth or guidance of any MB neuron type. We found that UNF promotes this process of developmental axon regrowth via the TOR pathway as well as a late axon guidance program via an unknown mechanism. We have thus uncovered a novel developmental program of axon regrowth that is cell autonomously regulated by the UNF nuclear receptor and the TOR pathway. Conclusions: Our results suggest that UNF activates neuronal re-extension during development. Taken together, we show that axon growth during developmental remodeling is mechanistically distinct from initial axon outgrowth. Due to the involvement of the TOR pathway in axon regeneration following injury, our results also suggests that developmental regrowth shares common molecular mechanisms with regeneration following injury. *Correspondence: oren.schuldiner@weizmann.ac.il Please cite this article in press as: Yaniv et al., Axon Regrowth during Development and Regeneration Following Injury Share Molecular Mechanisms, Current Biology (2012), http://dx.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 2004
Injured nerves regenerate their axons in the peripheral (PNS) but not the central nervous system (CNS). The contrasting capacities have been attributed to the growth permissive Schwann cells in the PNS and the growth inhibitory environment of the oligodendrocytes in the CNS. In the current review, we first contrast the robust regenerative response of injured PNS neurons with the weak response of the CNS neurons, and the capacity of Schwann cells and not the oligodendrocytes to support axonal regeneration. We then consider the factors that limit axonal regeneration in both the PNS and CNS. Limiting factors in the PNS include slow regeneration of axons across the injury site, progressive decline in the regenerative capacity of axotomized neurons (chronic axotomy) and progressive failure of denervated Schwann cells to support axonal regeneration (chronic denervation). In the CNS on the other hand, it is the poor regenerative response of neurons, the inhibitory proteins that are express...
Extrinsic and intrinsic determinants of nerve regeneration
Journal of tissue engineering, 2011
After central nervous system (CNS) injury axons fail to regenerate often leading to persistent neurologic deficit although injured peripheral nervous system (PNS) axons mount a robust regenerative response that may lead to functional recovery. Some of the failures of CNS regeneration arise from the many glial-based inhibitory molecules found in the injured CNS, whereas the intrinsic regenerative potential of some CNS neurons is actively curtailed during CNS maturation and limited after injury. In this review, the molecular basis for extrinsic and intrinsic modulation of axon regeneration within the nervous system is evaluated. A more complete understanding of the factors limiting axonal regeneration will provide a rational basis, which is used to develop improved treatments for nervous system injury.
European Journal of Neuroscience, 2001
We have investigated the hypothesis that the chemorepellent Semaphorin3A may be involved in the failure of axonal regeneration after injury to the ascending dorsal columns of adult rats. Following transection of the thoracic dorsal columns, ®broblasts in the dorsolateral parts of the lesion site showed robust expression of Semaphorin3A mRNA. In addition, dorsal root ganglion (DRG) neurons with projections through the dorsal columns to the injury site persistently expressed both Semaphorin3A receptor components, neuropilin-1 and plexin-A1. These ascending DRG collaterals failed to invade scar regions occupied by Semaphorin3A-positive ®broblasts, even in animals which had received conditioning lesions of the sciatic nerve to enhance regeneration. Other axon populations in the dorsal spinal cord were similarly unable to penetrate Semaphorin3A-positive scar tissue. These data suggest that Semaphorin3A may create an exclusion zone for regenerating dorsal column ®bres and that enhancing the intrinsic regenerative response of DRG neurons has only limited effects on axonal regrowth. Tenascin-C and chondroitin sulphate proteoglycans were also detected at the injury site, which was largely devoid of central nervous system (CNS) myelin, showing that several classes of inhibitory factors, including semaphorins, with only partially overlapping spatial and temporal patterns of expression are in a position to participate in preventing regenerative axonal growth in the injured dorsal columns. Interestingly, conditioning nerve injuries enabled numerous ascending DRG axons to regrow across areas of strong tenascin-C and chondroitin sulphate proteoglycan expression, while areas containing Semaphorin3A and CNS myelin were selectively avoided by (pre)primed axonal sprouts.
Regulation of Semaphorin III/Collapsin-1 Gene Expression during Peripheral Nerve Regeneration* 1
Experimental neurology, 1998
The competence of neurons to regenerate depends on their ability to initiate a program of gene expression supporting growth and on the growth-permissive properties of glial cells in the distal stump of the injured nerve. Most studies on intrinsic molecular mechanisms governing peripheral nerve regeneration have focussed on the lesion-induced expression of proteins promoting growth cone motility, neurite extension, and adhesion. However, little is known about the expression of intrinsic chemorepulsive proteins and their receptors, after peripheral nerve injury and during nerve regeneration. Here we report the effect of peripheral nerve injury on the expression of the genes encoding sema III/coll-1 and its receptor neuropilin-1, which are known to be expressed in adult sensory and/or motor neurons. We have shown that peripheral nerve crush or transection results in a decline in sema III/coll-1 mRNA expression in injured spinal and facial motor neurons. This decline was paralleled by an induction in the expression of the growth-associated protein B-50/GAP-43. As sema III/coll-1 returned to normal levels following nerve crush, B-50/GAP-43 returned to precrush levels. Thus, the decline in sema III/coll-1 mRNA coincided with sensory and motor neuron regeneration. A sustained decline in sema III/ coll-1 mRNA expression was found when regeneration was blocked by nerve transection and ligation. No changes were observed in neuropilin-1 mRNA levels after injury to sensory and motor neurons, suggesting that regenerating peripheral neurons continue to be sensitive to sema III/coll-1. Therefore we propose that a decreased expression of sema III/coll-1, one of the major ligands for neuropilin-1, during peripheral nerve regeneration is an important molecular event that is part of the adaptive response related to the success of regenerative neurite outgrowth occurring following peripheral nerve injury. 1998 Academic Press
Semaphorins in axon regeneration: developmental guidance molecules gone wrong?
Philosophical Transactions of the Royal Society B: Biological Sciences, 2006
Semaphorins are developmental axon guidance cues that continue to be expressed during adulthood and are regulated by neural injury. During the formation of the nervous system, repulsive semaphorins guide axons to their targets by restricting and channelling their growth. They affect the growth cone cytoskeleton through interactions with receptor complexes that are linked to a complicated intracellular signal transduction network. Following injury, regenerating axons stop growing when they reach the border of the glial-fibrotic scar, in part because they encounter a potent molecular barrier that inhibits growth cone extension. A number of secreted semaphorins are expressed in the glial-fibrotic scar and at least one transmembrane semaphorin is upregulated in oligodendrocytes surrounding the lesion site. Semaphorin receptors, and many of the signal transduction components required for semaphorin signalling, are present in injured central nervous system neurons. Here, we review evidenc...