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 processes each terminating in a myelin sheath. In order to achieve the production and directional assembly of this large amount of membrane, the cell spatially organizes its synthetic machinery through the redistribution of its cytoskeletal elements. This hypothesis will be tested by microscopic analysis of the distribution of cellular organelles and cytoskeletal elements in oligodendrocytes at various stages of myelin formation. Myelin components are regionally distributed within the oligodendrocytes and the myelin sheath. Thus, the synthesis of myelin requires sorting mechanisms by which specific myelin components are recognized by the oligodendrocyte cellular machinery and delivered to the site of myelin assembly. The sorting of myelin basic protein takes place at the level of its mRNA, which is transported down the processes to the myelin sheath in a complex associated with the oligodendrocyte cytoskeleton. We propose to characterize this complex by the use of in situ hybridization, immunocytochemistry, E.N. localization, and metabolic inhibitors. Our long term objectives are to delineate and characterize the various steps in myelin morphogenesis. 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 chemotherapy or viral infections.