Permissive and repulsive cues and signalling pathways of axonal outgrowth and regeneration

Successful axonal outgrowth in the adult central nervous system (CNS) is central to the process of nerve regeneration and brain repair. To date, much of the knowledge on axonal guidance and outgrowth comes from studies on neuritogenesis and patterning during development where distal growth cones constantly sample the local environment and respond to specific physical and trophic influences. Opposing permissive (e.g., growth factors) and hostile signals (e.g., repulsive cues) are processed, leading to growth cone remodelling, and a concomitant restructuring of the cytoskeleton, thereby permitting pioneering extension and a potential for establishing synaptic connections. Repulsive cues, such as semaphorins, ephrins and myelin-secreted inhibitory glycoproteins, act through their respective receptors to affect the collapsing or turning of growth cones via several pathways, such as the Rho GTPases signalling which precipitates the cytoskeletal changes. One of the direct modulators of microtubules is the family of brain-specific proteins, collapsin response mediator protein (CRMP). Exciting evidence emerged recently that cleavage of CRMPs in response to injury-activated proteases, such as calpain, signals axonal retraction and neuronal death in adult post-mitotic neurons, while blocking this signal transduction prevents axonal retraction and death following excitotoxic insult and cerebral ischemia. Regeneration is minimal in injured postnatal CNS, albeit the occurrence of some limited remodelling in areas where synaptic plasticity is prevalent. Frequently in the absence of axonal regeneration, there is not only an inevitable loss of functional connections, but also a loss of neurons, such as through the actions of dependence receptors. Deciphering the cues and signalling pathways of axonal guidance and outgrowth may hold the key to fully understanding nerve regeneration and brain repair, thereby opening the way for developing potential therapeutics.