The object of this proposal is to extend our understanding of th role of two tyrosine kinase containing receptors in the development and maturation of the oligodendrocyte. The two receptors we have studied are both expressed in mature oligodendrocytes or their precursors. The p185c neu protein is expressed on the early O-2A precursor and the p65/95 receptor is expressed on the late early and intermediate forms that differentiate into the mature oligodendrocyte. In cells which express both of these receptors, such as the glioblastoma B104, perturbation of p65/95 by antireceptor light chain or a reovirus hemagglutinin form causes the phosphorylation of p185c-neu suggesting that activation pathways might intersect. These receptors are relevant to growth and maturation of oligodendrocytes; and ligands which bind to them may be relevant to oligodendrocyte injury, or possibly, enhancement of remyelination in Multiple Sclerosis. We introduce an idea originally intimated by others that certain activated or retrovirally infected T cells might produce factors which disturb neural function. One of the factors we are studying, NAF, is derived from an HTLV-1 transformed human T cell and activates p185c-neu on oligodendrocyte precursors. We speculate that growth stimulating molecules, if inappropriately produced, might disturb oligodendrocyte growth and contribute to demyelination. In addition, under other circumstances, such factors might be beneficial for modifying other types of growth inhibiting injuries of oligodendrocytes. The activity of ligands and receptors to which they bind on oligodendrocytes is the basis for the studies described herein. The issues to be addressed include the biochemical basis of p185 and p65/95 perturbation of the oligodendrocyte precursor and their effects on oligodendrocyte maturation.
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