NEURAL CONTROL OF THE PREPUBERTAL OVARY

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The overall goal of this application is to elucidate the neuroendocrine mechanisms involved in the developmental regulation of ovarian function. The concept is proposed that the developing ovary is subjected to a "neuroendocrinotrophic" control effected by the interactive participation of the extrinsic innervation, an intragonadal source of neurotransmitters, and a family of neurotrophic genes previously believed to target only the nervous system for their biological actions. This concept stems from a series of observations demonstrating: a) the contribution of the extrinsic innervation to the regulation of ovarian steroidogenesis and follicular development, b) the involvement of nerve growth factor (NGF) in regulating ovarian development indirectly via its neurotrophic effects on the ovarian innervation, c) the ability of neurotransmitters contained in ovarian nerves to initiate the molecular differentiation of early granulosa cells at the onset of follicular growth, and d) the existence in the primate ovary of an intrinsic source of catecholamine biosynthesis. Further studies suggested that an enhanced activity of the ovarian sympathetic innervation may contribute to the etiology of polycystic ovarian syndrome, the most common ovarian pathology affecting women of reproductive age. While studying the role of NGF in supporting the ovarian innervation, it became apparent that the developing ovary not only synthesizes several members of the NGF family of neurotrophins, but unexpectedly, also expresses the tyrosine kinase receptors that mediate the biological actions of neurotrophins in the nervous system. The presence of such receptors in endocrine cells of the ovary implies that neurotrophins can directly affect ovarian function without the intermediacy of the innervation, and raises the intriguing possibility of an hitherto unsuspected role for neurotrophins in the control of ovarian development. The present application proposes a combination of physiological, cellular and molecular approaches to address this issue, and to define the contribution of each of the proposed "neuroendocrinotrophic" components to the regulation of specific developmental events in ovarian maturation. To this end, the following specific aims are proposed: 1. To examine the hypothesis that two neurotrophins, NGF and neurotrophin-4, play different, but complementary roles in the cytodifferentiation/ organizational process underlying the period of definitive ovarian histogenesis, at the time of follicular formation. 2. To examine the hypothesis that neurotransmitters and neurotrophins interact positively in promoting the molecular differentiation of granulosa cells during early follicular development. 3. To examine the hypothesis that activation of trkA receptors during the hours preceding the first ovulation contributes to the cytodifferentiation process leading to follicular rupture. 4. To examine the hypothesis that activation of ovarian NGF synthesis and that of its low-affinity receptor is a key component in the etiology of polycystic ovarian syndrome. 5. To characterize the molecular forms and cellular sources of tyrosine hydroxylase and dopamine-beta hydroxylase, the two key enzymes in catecholamine synthesis recently found to be expressed in the developing primate ovary.