OLIGODENDROCYTE ONTOGENY AND DIFFERENTIATION

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DESCRIPTION (From the Applicant's Abstract): The major function of the oligodendrocyte in the CNS is to produce myelin, the membrane sheath that envelops axons and is necessary for saltatory conduction. Our long term goal is to elucidate the process of myelination and its regulation. Myelin basic protein (MBP), a major structural component of the sheath, is essential for the formation of myelin. MBP is synthesized at its site of assembly in the myelin membrane. This is accomplished by transport of MBP mRNA from the nucleus to the cell body and down the cell processes and into the myelin sheath, followed by anchoring and translation. The short term goal of our research efforts is to elucidate this trafficking pathway. This will be accomplished by: Characterizing the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) A2, the essential trans-acting factor that recognizes the signal sequence for transport present in MBP mRNA; identifying other constituents of the MBP mRNA trafficking system and determining their role; characterizing the conditions under which MBP mRNA trafficking is blocked or enhanced, and delineating the steps in MBP mRNA translocation from the nucleus to the myelin membrane and pattern of regulation. Microinjection of live cell in culture, confocal microscopy, immunocytochemistry, Western blot, yeast two-hybrid system, co-immunoprecipitation and subcellular fractionation procedures will be used. Hypomyelination and demyelination have severe neurological consequences. Understanding the mechanism of mRNA trafficking is the first step in understanding how myelin is made a repaired throughout the life of an individual. This knowledge should lead to therapies, immunochemical or pharmaceutical for patients afflicted with demyelinating diseases of the CNS and PNS such as multiple sclerosis, Charcot-Marie-Tooth disease and Guillain-Barre syndrome, and for patients with demyelinating conditions following therapeutic irradiation and chemotherapy or viral infections.