NEURAL CONTROL OF THE PREPUBERTAL OVARY

本提案的总体目标是充实新出现的概念 发育中的卵巢，除了激素调节外， 由直接的神经影响所控制 在过去的支持期间， 我们发现了三个为本申请提供基础的发现。 我们证明：a）大鼠卵巢的交感神经支配是 正常卵巢功能所需，神经生长因子（NGF）是 对于这种神经支配的发育至关重要，B）大鼠卵巢能够 在缺乏外部神经支配的情况下产生儿茶酚胺，以及c） 交感神经支配的腺体发展开始之前， 卵泡发生 因此，本更新申请集中于NGF受体 （NGFrec），介导NGF、酪氨酸 羟化酶（TH），在儿茶酚胺生物合成中的限速步骤，和 卵泡发育早期卵巢的外在神经支配。 提出实验来定义的存在和可能的功能， 未成熟大鼠卵巢中NGF受体的表达及其对卵巢TH mRNA表达的影响 根据初步结果判断，其可能编码一种TH分子， 与肾上腺酶不同，并确定神经递质 包含在卵巢神经有助于卵泡的启动 阵 提出了进一步的研究来检验这一假设， 灵长类动物卵巢的神经支配也先于卵泡发生，因此 代表了哺乳动物早期生殖的基本机制 发展 为此，提出了以下具体目标： 建立NGFrec在卵巢中的存在和 非神经元卵巢细胞合成的受体，除了那些 由支配纤维表达，2）调查假设， 卵巢中的非神经元NGFrec的调节与那些 3）检查神经生长因子在神经末梢中表达的可能性， 除了其神经营养活性外， 4）确定细胞来源，调节和 卵巢TH mRNA的分子特征，其由 核糖核酸酶保护测定与肾上腺TH mRNA在 5 '端，5）以检验神经递质包含在 卵巢神经是卵巢发育的早期神经源性调节成分， 卵巢发育能够在卵巢之前启动卵泡形成 成为受促性腺激素控制，6）检查，与光和 电子显微镜，假设灵长类动物的卵巢成为 在卵泡发生开始之前受到神经支配， 神经建立与原始类固醇生成的早期解剖接触 在这些细胞被组织成滤泡结构之前，

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.