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Abstract

Spinal cord injury in higher vertebrates causes paralysis because injured neurons in the adult central nervous system (CNS) often atrophy or die, and fail to regenerate their severed processes ("axons"). In contrast, injured peripheral nervous system (PNS) neurons usually survive and regenerate their axons. One reason for successful PNS responses to axon injury ("axotomy") is that they undergo numerous changes in gene expression that enhance their intrinsic growth state. These changes include the upregulation of proteins required for axon growth, and down-regulation of non-essential proteins, such as those used mainly for neurotransmission. Similar changes in gene expression are generally only weak and transient in axotomized CNS neurons, which most likely contributes to their poor responses to injury. This thesis investigates the potential regulation of injury-induced changes in gene expression by neurotrophic factors (NTFs), small proteins important for development and maintenance of the nervous system. Three principal findings are presented here. Firstly, in axotomized PNS motoneurons, the down-regulation of non-essential proteins associated with neuronal maturation, such as neurotransmitter enzymes and neurofilaments appears to be due to the interrupted supply of target-derived neurotrophic factors. Secondly, in axotomized PNS. motoneurons, the robust up-regulation of regeneration-associated genes and cell body hypertrophy is enhanced by non-targetderived neurotrophic factors, most likely those released by Schwann cells and immune cells at the actual site of injury. In fact, a second axon injury (to stimulate release of these endogenous neurotrophic factors) was sufficient to actually reverse the severe cell body atrophy and up-regulate the regeneration-associated gene expression of chronically axotomized motoneurons. Thirdly, when exogenous neurotrophic factors were used to supplement a CNS spinal cord lesion site, which does not contain Schwann cells and has only limited invasion of immune cells, the regenerative cell body responses of axotomized CNS rubrospinal neurons were greatly enhanced. These findings provide insights into the signals regulating neuronal gene expression after injury, and identify neurotrophic factors at the site of axotomy as an important determinant of a neuron's regenerative response to injury.