Chong, MunSeng; (1993) Neural regeneration and the growth associated protein GAP-43. Doctoral thesis (M.D), UCL (University College London).

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Abstract

The failure of the mammalian central nervous system to regenerate following injury was recognized by early neuroscientists particularly Ramon Y Cajal. Cajal demonstrated that providing a peripheral nervous system environment to the central nervous system encouraged the growth of central axons. Since then, a lot of work has been done on this subject, resulting in a better understanding of the factors responsible for the failure of central, and the success of peripheral nervous system regeneration. The focus of my thesis has been to examine the role of a particular growth associated protein, GAP-43 in the regeneration of the mammalian peripheral and central nervous system, using the rat spinal cord and peripheral nerve as a model. GAP-43 is a phosphoprotein that is developmentally regulated and re-expressed following peripheral axotomy. It is concentrated in neuronal growth cones and possibly playing an important role in neural growth and synaptic plasticity. In the first part of the thesis, I have studied the expression of GAP-43 mRNA using an enzyme-linked in-situ hybridization technique. I have shown that GAP-43 is developmentally regulated at the transcriptional level and that the temporal pattern of expression in spinal cord and dorsal root ganglion cells differs in different cell types. After peripheral nerve injury in the adult, high levels of GAP-43 mRNA are re-expressed in spinal cord motorneurones and dorsal root ganglion cells and levels fall off with successful regeneration. Where regeneration is abortive, there is a finite period of GAP-43 mRNA re-expression. Axotomy of the central portions of primary afferents fail to cause GAP-43 re-expression, except in the first week where the site of injury is close to the dorsal root ganglion. This is likely to be due to post-surgical inflammation surrounding the ganglia. In a separate set of experiments, I have studied the expression of GAP-43 mRNA in Schwann cells of muscle motor end- plate after denervation and show that this phosphoprotein is not exclusively produced by nerve cells. The second part of my thesis has been a study into factor(s) involved in encouraging central nervous system regeneration. Using peripheral nerve grafts transplanted onto sectioned dorsal roots, I have shown that the provision of a peripheral environment results in the upregulation of GAP-43 mRNA expression in dorsal root ganglion cells. In addition, axons in the central portion of primary afferents grow into these grafts and express GAP-43 protein. I have also investigated the expression of GAP-43 mRNA in dorsal root ganglion cells and spinal cord after transplantation of freeze- killed peripheral nerve grafts onto tibial nerves. Limited regeneration of neurites lasting 6 weeks was seen but re-expression of GAP-43 mRNA continued even when regeneration into the acellular grafts has stopped. In conclusion GAP-43 is an important marker for neuronal growth and regeneration. However, GAP-43 re-expression alone appears to be insufficient to ensure regeneration, although the failure to re-express GAP-43 may be sufficient to abort regeneration. Successful regeneration in the central nervous system requires both an intrinsic response from axotomized neurons together with extrinsic trophic factors, and an appropriate cellular and substrate environment.

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