The vertebrate nervous system develops and functions through a set of cellular interactions. Among the most striking of these interactions is one that occurs between neurons and glia, and results in the elaboration of the myelin sheath, the electrical insulation that surrounds all rapidly conducting axons. For the glial cells that elaborate myelin, production of the sheath involves a drastic reorganization of both morphology and metabolism, including the induction and high-level expression of a set of genes and proteins unique to myelin-forming cells. This proposal is concerned with the identification and functional characterization of the genes that mediate glial cell differentiation and myelination. Specific questions addressed include: By what mechanisms are myelination-specific genes induced and regulated? What role do neurons play in these processes? What are the cis-acting regulatory elements of these genes that control their cell-specific transcription and what are the trans-acting proteins that bind these elements? When and where are myelination genes expressed during neural development? And what can we learn of the function of the proteins these genes encode? To address these and related questions requires both probes for the relevant genes and proteins, as well as the ability to manipulate the cellular environment and development of myelinating glia. The experiments described below therefore employ the techniques of eukaryotic molecular genetics and the in vitro culture of purified glial cells and cell lines, in conjunction with the application of recombinant DNA and antibody probes for glial- specific genes and proteins. The ultimate goal of this work is the delineation of the molecular pathway of myelin formation during normal development. Additionally, it may provide an understanding of glial gene expression and protein metabolism under circumstances in which glia are deprived of the influence of neurons, as occurs in central and peripheral neuropathies, and during episodes of demyelination and remyelination, as occur in Multiple Sclerosis.
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