The proposal is aimed at gaining new insight into the developmental processes that underlie the maturation of the reproductive hypothalamus and, hence, the onset of female puberty. Utilizing the rat as the animal model, experiments are proposed to examine the hypothesis that brain neuronotrophic factors regulate the development of the hypothalamic LHRH- secreting system, which culminates when a discharge of LHRH release triggers the first preovulatory surge of gonadotropins. To this end, the following specific aims are proposed. 1. To document the hypothesis that nerve growth factor (NGF) and transforming growth factor alpha (TGFalpha), as well as their respective receptors, are expressed in the hypothalamus, and to examine their contribution to the developmental regulation of LHRH secretion. 2. To examine the hypothesis that TGFalpha facilitates the morphological and functional differentiation of LHRH neurons and to determine whether NGF is trophic for LHRH neurons and/or a neuronal system regulatory to LHRH function. 3. To examine the hypothesis that hypothalamic trophic factors, and in particular the epidermal growth factor receptor EGFr/TGFalpha ligand system can influence LHRH synthesis by directly regulating transcriptional activity of the LHRH gene. 4. To examine the hypothesis that TGFalpha is one of the neuronotrophic factors that contribute to the peripubertal, gonadal-independent activation of LHRH release. The accomplishment of these aims depends on the team participation of one neuroendocrinologist, one molecular biologist, and two morphologists, and on the integrated use of neuroendocrine, neurobiology and molecular biology approaches.
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