Inhibitors of neuronal regeneration: mediators and signaling mechanisms

Neuritogenesis and its inhibition are opposite and balancing processes during development as well as pathological states of adult neuron. In particular, the inability of adult central nervous system (CNS) neurons to regenerate upon injury has been attributed to both a lack of neuritogenic ability and the presence of neuronal growth inhibitors in the CNS environment. I review here recent progress in our understanding of neuritogenic inhibitors, with particular emphasis on those with a role in the inhibition of neuronal regeneration in the CNS, their signaling cascades and signal mediators. Neurotrophines acting through the tropomyosin-related kinase (Trk) family and p75 receptors promote neuritogenesis, which appears to require sustained activation of the mitogen activated protein (MAP) kinase pathway, and/or the activation of phosphotidylinositol 3-kinase (PI3 kinase). During development, a plethora of guidance factors and their receptors navigate the growing axon. However, much remained to be learned about the signaling receptors and pathways that mediate the activity of inhibitors of CNS regeneration. There is growing evidence that neuronal guidance molecules, particularly semaphorins, may also have a role as inhibitors of CNS regeneration. Although direct links have not yet been established in many cases, signals from these agents may ultimately converge upon the modulators and effectors of the Rho-family GTPases. Rho-family GTPases and their effectors modulate the activities of actin modifying molecules such as cofilin and profilin, resulting in cytoskeletal changes associated with growth cone extension or retraction.