The objective of this umbrella project is to acquire a detailed understanding of the developmental program that culminates in myelin synthesis. We are particularly interested in obtaining molecular level information about the control of expression of both the myelin basic protein (MBP) and proteolipid protein (PLP) genes. To this end, we have cDNA cloned and sequenced both the human and mouse MBP and PLP mRNAs. We have used these characterized cDNAs to identify and study the organization of the genes encoding them. Our results demonstrate conclusively that the multiple forms of MBP and PLP found both in man and mouse originate through a mechanism of alternative splicing of the nacent gene transcript. During the current reporting period, we have completed the initial phases of the characterization of the promoter and enhancer regions of both the MBP and the PLP genes. We have made plasmid constructions using these cis acting elements and a gene whose expression is easily measured. These constructions have been introduced into the germ line of mice so that the tissue specificity of these cis acting elements can be verified in an in vivo animal model. Contrary to widely held beliefs, the gene encoding proteolipid protein is expressed in Schwann cells and their tumors. PLP mRNA was identified in human acoustic neuromas and rat and rabbit sciatic nerves using PLP cDNA as a probe. The proteolipid protein, itself, was shown to be present in rat and human sciatic nerve Schwann cells by immune fluorescent microscopy and Western blot analysis. Although easily detected in Schwann cell bodies, the PLP was not detected in the peripheral myelin, itself, suggesting that the PLP is preferentially excluded from this portion of the Schwann cell membrane.
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