The regulation of myelination by the p75-NFkB pathway

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DESCRIPTION (provided by applicant): Myelin is necessary for the rapid conduction of nerve impulses, the protection of axons from damaging agents, providing trophic support to neurons and regulating the ability of injured axons to regenerate. Hence, pathological conditions that cause demyelination such as Multiple Sclerosis, Guillian Barre Syndrome or nerve injury can have disastrous consequences for the afflicted individuals. Myelin is multilamellar structure produced by Schwann cells in the peripheral nervous system and oligodendrocytes in the CNS in response to axonal signals that have yet to be defined. Our overall objective is to elucidate the mechanisms regulating the formation of this essential neural structure. We recently demonstrated that activation of the transcription factor NFkB in pre-myelinating Schwann cells is essential for their differentiation into a myelinating phenotype. Inhibition or genetic deletion of NFkB in Schwann cells prevented myelin formation. The up stream activator of NFkB remains to be determined; however, the p75 neurotrophin receptor, which can activate this transcription factor, was recently shown to have an essential role in the process of myelination. During the development of the peripheral nervous system, p75 is highly expressed in pre-myelinating Schwann cells, but begins to decline as myelin forms and is difficult to detect in the mature, myelinating glia. Nevertheless, p75 is also expressed in the sensory neurons that become myelinated, thus it is unclear whether p75's critical function is specifically in Schwann cells, neurons or both. It is our overall hypothesis that p75 mediated activation of NFkB is required for Schwann cells to form myelin. We will investigate this proposal using transgenic animals and an in vitro myelination system of Schwann cells and sensory neurons in co-culture. Our specific objectives are: (1) Define the mechanisms of NFkB activation. (2) Investigate where p75 expression is required in order for myelin to form by use of a conditional gene deletion. (3) Determine the contribution of p75 to the endogenous NFkB activity in pre-myelinating Schwann cells. (4) Define the target genes of NFkB in Schwann cells through gene profiling by microarray and the analysis of promoters of myelin genes we have already identified as regulated by the transcription factor.