The overall goal of this proposal is to substantiate the emerging concept that the developing ovary, in addition to its hormonal regulation, is controlled by direct neural influences. During the past period of support we made three findings which provide the bases for the present application. We demonstrated that: a) the sympathetic innervation of the rat ovary is required for normal ovarian function, and nerve growth factor (NGF) is essential for development of this innervation, b) the rat ovary is able to produce catecholamines in the absence of extrinsic innervation, and c) the sympathetic innervation of the gland develops before initiation of folliculogenesis. Thus, this renewal application focuses on NGF receptors (NGFrec), the molecular entity that mediates the effects of NGF, tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, and the extrinsic innervation of the ovary during early follicular development. Experiments are proposed to define the presence and possible functions of NGF receptors in the immature rat ovary, to characterize ovarian TH mRNA which, as judged by preliminary results, may encode a TH molecule regulated differently than the adrenal enzyme, and to determine if neurotransmitters contained in ovarian nerves contribute to the initiation of follicular formation. Additional studies are proposed to test the hypothesis that innervation of the primate ovary also precedes folliculogenesis, thus representing a fundamental mechanism of early mammalian reproductive development. To this end, the following specific aims are proposed: 1) To establish the existence of NGFrec in the ovary and the ability of non-neuronal ovarian cells to synthesize the receptors in addition to those expressed by the innervating fibers, 2) to investigate the hypothesis that non-neuronal NGFrec in the ovary are regulated differently than those expressed in nerve terminals, 3) to examine the possibility that NGF -- in addition to its neurotrophic activity -- may affect the cytodifferentiation of follicular cells, 4) to define the cellular sources, regulation and molecular characteristics of ovarian TH mRNA, which as determined by ribonuclease protection assays, diverges from adrenal TH mRNA at the 5'terminus, 5) to test the hypothesis that neurotransmitters contained in ovarian nerves represent an early neurogenic regulatory component of ovarian development able to initiate follicular formation before the ovary becomes subjected to gonadotropin control, 6) to examine, with light and electron microscopy, the hypotheses that the primate ovary becomes innervated before initiation of folliculogenesis, and that the developing nerves establish early anatomical contacts with primordial steroidogenic cells before these cells become organized into a follicular structure.
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