The role of brain-derived neurotrophic factor (BDNF) in development and survival in the mammalian nervous system /

The nerve growth factor family of neurotrophins play multiple roles in both the developing and mature mammalian nervous systems. During development, neurotrophins are typically thought to act as retrogradely-derived signals that mediate the survival of innervating neurons. However, recent studies have highlighted different mechanisms of delivery and multiple functions for certain neurotrophins, extending their scope of biological activity beyond that suggested by the neurotrophic hypothesis. This thesis highlights two novel roles for the neurotrophin, brain-derived neurotrophic factor (BDNF), in the mammalian nervous system, and the mechanisms by which these events are mediated.First, we show that BDNF is anterogradely transported in central noradrenergic neurons to regulate the development of target neuron populations such as the neocortex, and to mediate the survival of injured motor neurons. This provides the first evidence of a functional role for anterogradely-derived BDNF during the survival and development of target neuron populations. Two transgenic mouse constructs were used to determine the role of anterogradely-derived BDNF; the previously characterized dopamine beta-hydroxylase (DBH):BDNF transgenic mice, and Talpha1:nlacZ transgenic mice which have been extensively characterized within the scope of this thesis.Second, we show that BDNF mediates apoptosis via the p75NTR in neurons lacking TrkB. Indeed, BDNF-mediated p75NTR activation results in increased sympathetic neuron death in vitro, and ablation of BDNF and p75 in vivo, (BDNF-/- or p75-/- mice), results in an increased number of SCG neurons following the period of naturally occurring cell death. Together, these data indicate that p75NTR can mediate apoptosis, and that this mechanism is essential for naturally-occurring cell death.We also show that the tumor suppressor protein, p53, is essential during naturally-occurring sympathetic neuron death, and that p53 protein levels are increased following both BDNF-mediated activation of p75, and NGF withdrawal. Moreover, we postulate that both the p75-mediated and NGF withdrawal-induced upregulation of p53 is mediated by the MEKK-JNK pathway. The p53 tumor suppressor protein has been shown to play an apoptotic role in several cell types, including in neurons exposed to external stressors, such as excitotoxicity and DNA damage. This is the first time p53 has been demonstrated to play an apoptotic role during the development of the mammalian nervous system