The vertebrate nervous system develops and functions through a set of cell-cell interactions. Among the most striking of these interactions is that which occurs between neurons and glia, and results in the elaboration of the myelin sheath, the electrical insulation which surrounds rapidly conducting axons. For the glial cells which elaborate myeline, production of the sheath entails 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 an identification of the cis and trans-acting elements which mediate activation and expression of the major myelin genes, and with an analysis of the function of the proteins these genes encode. Specific questions addressed by this proposal include: by what mechanisms are the major myelin genes induced? What role do axons play in this process? What are the cis-acting regulatory regions of these genes which control their cell-specific transcription? When and where are the major myelin genes expressed during neural development? And what can we learn of the function of the proteins that 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 of glial cells. 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 the major myelin 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 cell 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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