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Title: The role of NFκB-dependant gene expression in regulating the growth of developing peripheral neurons
Author: Hale, Valerie Anne
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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The principal aim of this thesis was to investigate the role of nuclear factor-kappa B (NF-κB) in the developing nervous system. NF-κB is a ubiquitously expressed transcription factor that plays a key role in regulating the expression of genes involved in a variety of cellular processes, including innate and adaptive immune responses, stress responses, cell survival, proliferation and differentiation. In the nervous system, NF-κB plays a role in regulating neuronal survival and has been implicated in learning and memory. In sensory neurons of the nodose ganglion of newborn mice cultured with BDNF, inhibiting NF-κB activation with super-repressor IκB-α, BAY 11-7082 (IκB-α phosphorylation inhibitor) or N-acetyl-Leu-Leu-norleucinal (proteosomal degradation inhibitor) or inhibiting NF-κB transcriptional activity with κB decoy DNA substantially reduced neurite arbour size and complexity while having no effect on survival. This novel role of NF-κB signalling in regulating neurite growth and morphology was found to be restricted to neurons cultured from mice between the ages of E18 and P1, a phase of development immediately after the phase of naturally occurring neuronal death when the processes and connections of the remaining neurons are extensively modified and refined. Monitoring NF-κB dependent transcriptional activity with a GFP reporter revealed a basal level of activity that was unaffected by BDNF. NF-κB was also found to be involved in promoting neurite growth from nodose neurons grown with CNTF, but not when these neurons were grown with the related cytokine LIF. Investigating the potential role of NF-κB signalling in regulating the growth of sympathetic neurites was complicated by the fact that NF-κB signalling is involved in mediating the survival-promoting effects of NGF, the neutrophin that promotes the survival of these neurons during development. To circumvent this problem, caspase inhibitors were used to prevent the death of superior cervical ganglion neurons in which NF-κB activation was prevented using either the inhibitor peptide SN50 or BAY 11-7082. These treatments resulted in significantly smaller neurite arbors seen in the presence of NGF, suggesting that NF-κB also plays a role in regulating the growth and complexity of developing sympathetic neurons.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available