Signaling Pathways Regulating Ovarian Follicle Formation

成功妊娠结局的一个基本决定因素是卵子的质量 受精形成受精卵。反过来，卵母细胞的健康状况是卵泡环境的直接反映。 以及生殖细胞和体细胞支持细胞之间的相互作用，这些支持细胞将卵母细胞培养成排卵。这个 已提出的研究探讨了卵泡的形成，并适用于了解如何 维持卵母细胞的健康，以及卵泡组装异常如何可能导致不孕不育。 这项研究调查了关键的发育信号通路在建立自我保护机制中的作用。 卵泡池。在卵巢器官发生过程中，生殖细胞合胞体或“巢”发生分解，形成 支持成年后生殖的原始毛囊。破坏生殖细胞分解的药物 巢和卵泡的形成对生殖健康有不利影响。我们的研究和别人的研究 确认Notch、激活素和雌激素信号在生殖细胞巢破裂和正常中起重要作用 卵泡在卵巢中的形成，并进一步揭示了这些途径的错误调节导致 异常卵泡的形成。我们假设这些信号中的每一个都在 卵泡形成，1)Notch调节颗粒-生殖细胞相互作用，促进颗粒细胞 同一性，2)激动素刺激颗粒细胞增殖，3)雌激素部分抑制破巢。 通过它对Notch和激活素信号的交叉调节。我们建议调查这些新角色，如 以及检测这些信号通路在新生小鼠卵巢中的整合。目标1将升级 一种新的体外卵巢培养系统以及条件基因敲除小鼠以研究其作用机制 哪种Notch信号调节体细胞颗粒前细胞功能并促进生殖细胞巢的破裂 和毛囊形成。目标2将利用卵巢培养系统以及基因表达谱 方法：建立激活素信号调节卵巢细胞的机制和靶基因 死亡或增殖，促进卵泡的形成。目标3将研究这两者之间的交叉监管 决定雌激素是否抑制生殖细胞巢破裂的信号通路是 通过Notch和激活素信号通路的相互作用来调节。关于信号转导的研究 在发育中的卵巢中调节生殖细胞和体细胞功能和相互作用的途径， 影响能够成熟和排出健康卵母细胞的卵泡形成的过程，将 当然可以增强我们识别、理解并最终治疗对我们不利的疾病或紊乱的能力 影响卵泡健康和妊娠结局。我们预计，本文件中描述的基础研究 该提案将有助于这一重要努力，并最终将促进人类生殖健康。

A fundamental determinant of a successful pregnancy outcome is the quality of the oocyte that will be fertilized to form the zygote. The health of the oocyte is, in turn, a direct reflection of the follicle environment and the interactions between germ cells and somatic support cells that nurture the oocyte to ovulation. The studies proposed invesfigate the formation of the ovarian follicle, and are applicable to understanding how the health of the oocyte is maintained and how aberrations in follicle assembly might contribute to infertility. This research investigates roles for key developmental signaling pathways in the establishment of the inifial follicle pool. During ovarian organogenesis, germ cell syncytia, or 'nests' undergo breakdown to form the primordial follicles that will support reproducfion in the adult. Agents that disrupt breakdown of germ cell nests and follicle formation have adverse impacts on reproductive health. Our studies and those of others idenfify Notch, activin and estrogen signaling as being important for germ cell nest breakdown and normal follicle formation in the ovary, and furthermore reveal that mis-regulation of these pathways results in the formation of aberrant follicles. We hypothesize that each of these signals play important but distinct roles in follicle formation, with 1) Notch regulafing granulosa-germ cell interactions and promoting granulosa cell identity, 2) acfivin sfimulafing granulosa cell proliferafion, and 3) estrogen inhibifing nest breakdown in part through its cross-regulation of Notch and activin signaling. We propose to investigate these novel roles, as well as to examine the integrafion of these signaling pathways in the neonatal mouse ovary. Aim 1 will ufilize a novel ex vivo ovary culture system as well as conditional knockout mice to investigate mechanisms by which Notch signaling regulates somatic pre-granulosa cell function and facilitates germ cell nest breakdown and follicle formafion. Aim 2 will utilize the ovarian culture system, as well as gene expression profiling approaches, to establish mechanisms and target genes by which activin signaling regulates ovarian cell death or proliferation and enhances follicle formation. Aim 3 will examine cross-regulation between these signaling pathways to determine if the repressive effects of estrogen on germ cell nest breakdown are mediated by interacfions with the Notch and activin signaling pathways. Studies invesfigafing the signaling pathways that regulate germ cell and somatic cell functions and interactions in the developing ovary, processes which impact the formation of follicles capable of maturing and ovulafing a healthy oocyte, will certainly enhance our ability to identify, understand and eventually treat diseases or disorders that adversely affect follicle health and pregnancy outcome. We anticipate that the basic research studies described in this proposal will contribute to that important effort and will eventually advance human reproductive health.