The mechanisms by which developing neurons direct axonal growth to target cells and form functional connections and the role such interactions play in cell survival and maturation are key issues in developmental neurobiology. Elucidation of the mechanisms controlling these interactions is essential for understanding not only normal maturation of the nervous system, but also pathological conditions that may result from abnormalities in such interactions. The research program proposed will investigate these mechanisms in greater depth. The primary objective is to isolate and characterize factors which control neuronal survival, axon outgrowth and biochemical differentiation of autonomic neurons. Using a combination of extremely sensitive and specific histochemical and radiochemical techniques, we then propose to define the role of these target-derived factors in the biochemical and morphological development of innervating neurons during critical periods of embryonic and fetal development. More specifically, we plan to: (1) purify and characterize the new neuronal growth factor previously isolated from mouse-heart-cell conditioned medium; (2) employing the pure conditioned medium factor, raise specific antibodies to examine the role of the factor in normal neuronal development through administration of specific antibodies both in culture and in vivo; (3) examine, in particular, the relative requirements for this conditioned medium factor and the well-characterized nerve growth factor in the development of embryonic sympathetic neurons in tissue culture. This research will help in understanding such developmental diseases as Familial Dysautonomia and Werdnig-Hoffman's disease. Isolation and characterization of specific molecules which stimulate and direct nerve growth will provide insights into nerve regeneration; such molecules may well serve in the treatment of patients suffering from nerve injury.
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