DEVELOPMENT REGULATION OF MYELIN BASIC PROTEIN GENE

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Myelin basic protein (MBP) constitutes more than 30% of the proteins of the myelin sheath in the central nervous system and 10% of these proteins in the peripheral nervous system. MBP is produced exclusively in glial and Schwann cells in the central and peripheral nervous systems, respectively. Recent studies have shown that a single gene encodes the family of MBPs and that the various forms of MBPs are governed by a mechanism of alternative splicing of the mRNA. Expression of MBPs is known to be differentially regulated during brain development. However, the mechanisms that govern tissue-specific transcription of this gene during myelination remain unknown. Analysis of the MBP regulatory region revealed that a small 11-nucleotide sequence located in the proximal activating sequence position -14 to -50 with respect to the RNA start site significantly contributes to the cell-specific activation of MBP in glial cells. The central goal of the research outlined in this proposal is to identify the molecular pathway by which MBP gene is transcriptionally regulated in glial cells. The experimental design includes: (1 ) identification of the regulatory-factor(s) that in concert with the proximal sequence control MBP promoter in cell- and stage-specific manner, (2) molecularly cloning the genes encoding this regulatory protein and investigating structure and function of this protein, (3) analyzing expression of this protein during brain development. The information gained from these analyses should increase our understanding of the mechanisms that modulate transcription of the genes in neural cells.