Mason, Matthew Robert James; (2001) Growth-associated molecules and axonal regeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

An important aspect of successful axonal regeneration is the neuronal response to axotomy. In order to characterise the changes in gene expression associated with axonal regeneration, expression of mRNAs for three candidate regeneration-associated molecules, SCG10, CAP-23 and FKBP12, along with the prototypical growth-associated molecule GAP-43, was examined by in situ hybridisation (ISH). SCG10 and CAP-23 were shown to be upregulated in regenerating neurons following sciatic nerve injury. Expression was downregulated by 6 weeks postoperation when regrowing axons have reached their targets, unless this was prevented by ligation of the injured nerve. Dorsal rhizotomy did not provoke any upregulation. All three candidate molecules were upregulated by CNS neurons regenerating axons into peripheral nerve grafts implanted into either the thalamus or the cerebellum, identified by retrograde labelling. These molecules therefore appear to be coregulated with GAP-43. A study was also made of the effects of overexpression of GAP-43 in transgenic mice on regeneration in circumstances in which the axotomy- induced gene upregulation in the injured neuron is minimal and insufficient to promote regeneration. GAP-43 overexpression in primary sensory neurons failed to augment consistently regeneration or sprouting following injury of the ascending dorsal columns in the spinal cord, or injury to the dorsal roots. Compared to wild-type controls, enhanced growth was sometimes seen after lumbar dorsal column injuries, while after thoracic dorsal column injury less growth was observed. Finally, the response to axotomy of neurons projecting down the spinal cord was characterised. Using retrograde labelling and ISH, expression of a panel of axotomy-associated genes was examined in corticospinal neurons following axotomy in the cervical cord or in the cortex, and in rubrospinal neurons following cervical axotomy. Corticospinal neurons showed no response to distal axotomy, but upregulated GAP-43, SCG10, c-jun, ATF3, L1 and CHL1 following proximal axotomy. Rubrospinal neurons clearly upregulated only L1, c-jun and ATF3.

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