The Development of the nervous system is dependent on a host of proteins which influence a variety of differentiative events. We have discovered one such factor which appears to regulate several developmental processes including mitosis of embryonic neuroblasts, differentiation of neurotransmitter traits in post-mitotic neurons, and expression of the trophic factor, nerve growth factor NGF, in glial cells of the central nervous system. This membrane-derived differentiating factor (MDF), extracted from rat spinal cords, has recently been purified to homogeneity. The goal of this project is to determine the critical role of MDF during development and to elucidate the molecular mechanisms underlying neuronal responses to the factor. Using amino acid sequence data from the purified factor, we plan to clone and sequence the cDNA that encodes MDF. This cDNA as well as antisera generated against MDF will be used to characterize its distribution and ontogeny by immunohistochemistry, and Northern blots to determine potential roles and sites of action. The antisera will also be used to disrupt the normal function of MDF to examine its role in vivo. To begin defining the molecular mechanisms involved in the various activities, 125I-MDF binding assays will be employed to identify and characterize its specific receptor(s). Our studies may provide information concerning the molecular basis for such congenital neurologic diseases as Familial Dysautonomia and dystonia musculorum deformans. Investigation of novel factors such as MDF and underlying molecular mechanisms may provide an entirely new class of therapeutic agents to treat birth defects.
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