Oligodendrocyte ontogeny and differentiation

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DESCRIPTION (provided by applicant): The major function of the oligodendrocyte in the CNS is to produce myelin that envelops axons and allows fast saltatory conduction of nerve impulses. Our long-term goal is to elucidate the process of myelination and its regulation. Since myelin basic protein (MBP) is a major and essential component of myelin we are focused on analyzing the mechanisms that control its expression. MBP is synthesized at its site of assembly in myelin. This is accomplished by transport of its mRNA from the nucleus to the cell body, and further down the cell processes and into myelin where it is anchored and translated. Our aims are to identify the elements in MBP mRNA that regulate its translation, the proteins that bind to these elements and their mode of action, and characterize the sites of MBP mRNA translation and the local factors that are necessary to initiate it. Failure to achieve full remyelination in the presence of adequate number of premyelinating oligodendrocytes in diseases such as multiple sclerosis may be due to the lack of receptivity on the part of the oligodendrocyte, lack of myelination signals on the part of the neuron, or to inhibiting conditions for myelination created by other cell types such as astrocytes. The latter conditions appear to be at play in multiple sclerosis and may have a direct negative effect on MBP expression. In order to accomplish the proposed aims the effects of deletion of translation regulatory elements in MBP mRNA, and knockdown of their specific RNA binding proteins will be assessed in an in vivo translation assay in cultured oligodendrocytes, and the characterization of protein-protein interactions by biophysical methods, and immnunological analysis of translation sites will be performed in cultured oligodendrocytes and in myelin fractions. Several diseases, such as multiple sclerosis, viral infections, or post-radiation symptom exist in humans that are due to the loss of myelin in the brain and the spinal cord. Patients have difficulty walking or doing daily chores. Myelin is a membrane that envelops the axon which is the part of the neuron responsible for nerve conduction. Our research focuses on finding out how myelin is made and how it can be repaired, possibly by the use of pharmacological drugs, so that patients could regain the ability to participate in normal life activities.