OLIGODENDROCYTE ONTOGENY AND DIFFERENTIATION

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Myelin is the multilamellar membranous sheath that surrounds axons in the CNS and the PNS, contributing to fast conduction of nerve impulses by saltatory conduction. In the CNS, the oligodendrocyte synthesizes, assembles and maintains the myelin sheath as a complex anatomical and functional structure. Each oligodendrocyte extends several dendritic processes each terminating in a myelin sheath. Myelin components are regionally distributed within the oligodendrocyte by translocation, and assembled at the site of myelin formation. The synthesis of myelin thus requires sorting mechanisms by which specific myelin components are recognized by the oligodendrocyte cellular machinery and delivered to the site of myelin assembly. This process may be regulated by neuronal signals upon interaction of an oligodendrocyte dendrite with an axon. We propose to use cell culture, genetic mutations, biochemical, immunochemical, biophysical and molecular biology techniques to study the mechanisms regulating the assembly of myelin basic protein, a major structural component of myelin, into the oligodendrocyte myelin membrane during oligodendrocyte differentiation in primary culture with neurons. Our long term objectives are to delineate the various steps in myelin morphogenesis, to determine their pattern of regulation and identify the molecular mechanisms underlying them. A better understanding of the process of myelin formation, and eventually of myelin maintenance and repair, could lead to therapies, immunochemical, pharmaceutical or genetic, for patients afflicted with demyelinating diseases of the CNS and PNS such as multiple sclerosis and Guillain-Barre syndrome, and for patients with demyelinating conditions following therapeutic irradiation and viral infections.