Neuronal intrinsic barriers for axon regeneration in the adult CNS

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A major reason for the devastating and permanent disabilities after spinal cord and other types of CNS injury is the failure of injured axons to regenerate and to re-build the functional circuits. Thus, a long-standing goal has been to develop strategies that could promote axon regeneration and restore functions. Recent studies revealed that simply removing extracellular inhibitory activities is insufficient for successful axon regeneration in the adult CNS. On the other side, evidence from different species and different models is accumulating to support the notion that diminished intrinsic regenerative ability of mature neurons is a major contributor to regeneration failure. This review will summarize the molecular mechanisms regulating intrinsic axon growth capacity in the adult CNS and discuss potential implications for therapeutic strategies.

Introduction

Understanding why injured axons cannot regenerate after injury in the adult mammals has been a major challenge for both basic and clinical neuroscientists. Previous elegant studies by David and Aguayo showing that some injured CNS axons were able to grow into a permissive graft transplanted to the lesion site suggested that inhibitory activities in the lesion sites might be primarily responsible for preventing axon regeneration [1]. Thus, extensive studies in the past decades have been aimed at characterizing the molecular identities and functional mechanisms of these inhibitors. As a result, multiple molecules highly inhibitory to axon growth have been identified. They are associated with either myelin debris (e.g. MAG, Nogo-A, and Omgp), or with glial scar formation (e.g. CSPG and tenasin) [2, 3, 4, 5, 6]. Signaling pathways for these inhibitors have also been discovered. For example, a recent study suggests that a receptor tyrosine phosphatase acts as a functional receptor for CSPGs [7]. However, removing these molecules by genetic deletions or pharmacological inhibitions only allows limited sprouting, but is not sufficient for long-distance axon regeneration [5, 8]. These observations demand re-consideration of the intrinsic regenerative ability of mature neurons.

It is known that axon re-growth involves expressions of regeneration-associated genes (RAGs) such as GAP-43, Cap23, Arg1, and Sprr1a. In order to initiate the transcription program for axon regeneration, an injury signal is first generated by the lesioned axon and relayed to the neuronal soma (Figure 1a). However, not all neurons respond to injury signals in the same way. Whether successful axon regeneration could occur depends on the intrinsic competence of injured neurons in launching a growth program (Figure 1b). Recent studies from C. elegans, zebrafish, and rodents revealed the possible molecular identities of injury signals and competence determinants.

Section snippets

Injury signals

Upon axotomy, different changes could occur at the injured axonal terminal, along the axon shaft, as well as in the neuronal soma. For example, the lesion site may have rapid ion influxes. In cultured neurons, axotomy leads to a significant increase in local calcium concentrations that rapidly trigger various responses in the soma [9]. At least in Aplysia, such calcium increase is important for initiating axonal re-growth program [10, 11]. In addition to these acute changes, extensive evidence

Neuronal competence of axon regeneration

Obviously, CNS neurons differ in their responses to injuries and injury-induced signals. While some axotomized neurons undergo cell death, those that survive the injuries differ in their abilities to initiate axon regeneration. Thus, an important question is what determines the intrinsic competence of neurons to regenerate injured axons.

References and recommended reading

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