Developmental changes in the trophic factor responses of peripheral nervous system neurons
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The aim of this project was to determine the neurotrophic factor survival requirements of PNS neurons during development and to clarify the role of certain receptors in mediating responsiveness. Members of the neurotrophin family of neurotrophic factors (NGF, BDNF, NT3 and NT4/5) and neurotrophic cytokines (CNTF, LIF, OSM, IL-6 and CT-1) were studied. The activity of a recently identified neurotrophin, NT4/5, was investigated in vitro. In cultures of mouse neurons, mammalian NT4/5 promoted the survival of the same kinds of neurons as BDNF and was as potent as BDNF, which is consistent with the action of both neurotrophins on the same receptor, TrkB. However, both mammalian NT-4/5 and the Xenopus homologue were less potent than mammalian BDNF on chicken embryo neurons, which is consistent with the lower evolutionary conservation of NT4/5. Interestingly, mammalian NT4/5 exhibited differences in potency on certain populations of chicken neurons that responded equally well to BDNF, and this may reflect differences in TrkB receptors in these different populations of neurons. To clarify the role of the common neurotrophin receptor in modulating the response of neurons to NGF, I then compared the actions of NGF with a mutated NGF protein that binds to TrkA, but does not bind to p75. At subsaturating concentrations, the NGF mutant was less effective than NGF in promoting the survival of embryonic sensory neurons and postnatal sympathetic neurons but was equally effective as NGF in promoting the survival of embryonic sympathetic neurons, indicating that binding of NGF to p75 enhances the sensitivity of NGF-dependent neurons to NGF at certain stages of development. To investigate if neurotrophic cytokines act on developing sensory neurons, I studied their effects in vitro. Whereas trigeminal neurons were responded to cytokines in the late fetal period, nodose neurons were supported by these factors throughout embryonic development. These findings indicate that different populations of PNS neurons display different patterns of responsiveness to neurotrophic cytokines during development.
Thesis, PhD Doctor of Philosophy
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