WNT and gonadotropin mediated regulation of ovarian steroidogenesis

描述（由申请人提供）：WNT信号分子家族已被确定为成年女性正常卵巢功能的潜在关键调节因子。众所周知，早期卵巢发育需要WNT蛋白，缺乏Wnt4的小鼠卵巢性别逆转，表达与睾丸发育相关的基因，出生时卵母细胞数量减少。此外，在颗粒细胞特异性等位基因编码组成活性-catenin的小鼠中，-catenin信号传导失调会导致生育力低下和晚发性颗粒细胞肿瘤的发生。在成年啮齿动物卵巢中已经报道了WNT和Frizzled家族的几个成员的表达和激素调节，并且WNT信号通路的下游调节因子-catenin已被证明在卵巢类固醇生成中发挥作用。此外，颗粒细胞中¿-连环蛋白的减少损害了FSH对芳香化酶mRNA的刺激和由此产生的雌二醇的产生。尽管越来越多的证据表明WNT信号通路在调节卵巢发育和类固醇产生中的重要性，但对于WNT在成年卵巢中的调节作用知之甚少。确定其他因素和机制，如WNT，有助于卵巢类固醇的产生，将有助于了解这些信号如何影响健康和疾病中的雌激素水平。我们的长期目标是描述成年卵巢中WNT信号的调节机制。本应用的直接目标是确定颗粒细胞WNT信号通路的特异性靶点，并描述这些靶点是如何被激素调节的。为实现这一申请的总体目标，将追求以下具体目标：确定FSH和WNT共同调节最终诱导卵巢雌二醇产生的芳香酶基因表达的机制。2. 利用微阵列分析研究颗粒细胞中受WNT和FSH调控的共同基因网络，绘制大鼠颗粒细胞原代培养中的基因表达谱。这项研究将提供新的靶点和策略，以扩大我们对卵泡发生的激素调节的认识，并可以改善女性因素不孕和卵巢病理的治疗。

DESCRIPTION (provided by applicant): The WNT family of signaling molecules has been identified as potential key regulators of normal ovarian function in the adult female. It is known that WNT proteins are required for early ovarian development and that mice lacking Wnt4 have sex-reversed ovaries, express genes associated with testes development and exhibit a reduced number of oocytes at birth. Additionally, misregulated ¿-catenin signaling in mice with granulosa cell-specific alleles encoding constitutively active ¿-catenin results in subfertility and the development of late onset granulosa cell tumors. Expression and hormonal regulation of several members of the WNT and Frizzled families have been reported in the adult rodent ovary and the downstream regulator of the WNT signaling pathway, ¿-catenin, has been shown to play a role in ovarian steroidogenesis. Moreover, reduction of ¿-catenin in granulosa cells compromises FSH stimulation of aromatase mRNA and resultant estradiol production. Despite emerging evidence as to the importance of the WNT signaling pathway in regulating ovarian development and steroid production, very little is known about the regulation of WNTs in the adult ovary. Identification of additional factors and mechanisms, such as WNT, that contribute to ovarian steroid production will provide insight to how these signals may impact estrogen levels in health and disease. Our long-term goal is to describe the mechanisms regulating WNT signaling in the adult ovary. The immediate goal of this application is to determine granulosa cell specific targets of the WNT signaling pathway and delineate how these targets are hormonally regulated. To accomplish the overall objective of this application the following specific aims will be pursued: 1. Determine the mechanisms by which FSH and WNT work together to regulate aromatase gene expression which is ultimately responsible for induction of ovarian estradiol production. 2. Investigate the common network of genes regulated by WNT and FSH in granulosa cells using microarray analysis to map the gene expression profiles in primary cultures of rat granulosa cells. This research will provide new targets and strategies to expand our knowledge about hormonal regulation of folliculogenesis and could improve treatments for female factor infertility and ovarian pathologies. PUBLIC HEALTH RELEVANCE: In humans, local and circulating estrogen levels influence numerous physiological and pathological processes including fertility and sexual behavior, bone remodeling and the development of various endocrine cancers. WNTs comprise a family of secreted glycoproteins that are key extracellular signaling proteins necessary for early ovarian development and steroidogenesis; aberrant regulation of the downstream co-activator of WNT signaling, ¿-catenin has been shown to cause cancer in a number of tissues including granulosa cells. Understanding the role of WNT/ ¿-catenin in the ovary and how this pathway converges with other extracellular signals will allow greater perspective on how these signals impact follicular maturation and estrogen levels in health and disease.