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Roles for NFkappaB, PHD3 and neural activity in the development of the peripheral nervous system

Gallagher, Denis J. 2008. Roles for NFkappaB, PHD3 and neural activity in the development of the peripheral nervous system. PhD Thesis, Cardiff University.

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In the developing peripheral nervous system, neuronal survival and axonal growth are regulated to a large extent by neurotrophic factors acting via intracellular signalling cascades that are not fully understood. Here, I describe crucial roles for the nuclear factor-kappa B (NFκB) transcription cascade and the cellular oxygen sensor proline hydroxylase domain 3 (PHD3) in the regulation of axonal growth and neuronal survival during the phase of target field innervation, and I describe a novel role for purinergic signalling in promoting neuronal survival at a later stage of development. Using sensory neurons of the nodose ganglion, I show that distinct NFκB activation mechanisms are responsible for neurite growth promoted by ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF). Whereas a non-canonical NFκB signalling pathway that requires tyrosine phosphorylation of IkBo. is crucial for CNTF-promoted growth, canonical signalling that requires serine phosphorylation of IicBa contributes to BDNF-promoted growth. Using sympathetic neurons of the superior cervical ganglion of wild type and PHD3-deficient mice, I show that PHD3 exerts a negative regulatory effect on neuronal survival and neurite growth, implicating oxygen sensitive pathways in the regulation of sympathetic neuron development. Despite increased numbers of sympathetic neurons in PHD3-deficient mice there was decreased target innervation density and defective sympathetic function. Finally, in nodose neurons I describe roles for depolarization and purinergic signalling in promoting neuronal survival during a window of development as the neurons begin to lose their dependence on BDNF for survival.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
ISBN: 9781303213137
Date of First Compliant Deposit: 30 March 2016
Last Modified: 12 Feb 2016 23:12

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