| Popis: |
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. |
