The focus of this grant is on the role of one particular transcription factor, SCIP/tst-1/Oct-6, in the development of oligodendrocytes. The logic of studying transcription factors in the process of differentiation is clear; differentiation requires changes in the expression of many genes, transcription factor regulate gene expression, so that transcription factors regulate differentiation. The central hypothesis is that SCIP/tst- 1/Oct-6 plays an important role in the regulation of early oligodendrocyte development. Such a role is in keeping with the known roles of the prototypes of POU family of transcription factors, Pit-1, Oct, and Unc, which regulate the differentiation of several cell types. I have shown that SCIP/tst-1/Oct-6 is transiently expressed in oligodendrocytes, at an early state when they have differentiated from neural-glial stem cells, but have not acquired the phenotype of immature oligodendrocytes. Whether SCIP?tst-1/Oct-6 is necessary and sufficient of oligodendrocyte differentiation will be tested directly by examining oligodendrocyte development in SCIP/tst-1/Oct-6""""""""knock-out"""""""" mice, and by over-expressing SCIP/tst-1/Oct-6 in neural-glial stem cells with an adenovirus vector, respectively. This work is directly relevant to diseases that affect myelin, the most common of which is multiple sclerosis (MS). Oligodendrocytes are the only myelinating cells of the CNS, and the recovery from an attack of MS is probably limited, at least in part, by the limited amount of remyelination that occurs. It is unclear why remyelination is limited, aas large numbers of immature oligodendrocytes are found in fresh lesion in the brains of MS patients. Thus, if we understood the regulation of oligodendrocyte development, then we would potentially be able to improve remyelination in experimental models of remyelination, and finally in patients.
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