The Role of FOS in the Ovary

摘要 了解排卵和随后的黄体（CL）形成的细胞事件是 至关重要，因为这些生物过程为我们调节女性的能力提供了基础。 生育排卵前促性腺激素激增诱发细胞事件的基本基石 排卵和CL的形成是特定转录因子的表达。然而，我们对 促性腺激素诱导的关键转录因子的特性和调节作用仍然有限。 最近的一项研究揭示了激活蛋白-1（AP-1）转录因子家族的一个成员FOS （又称c-fos），作为参与卵泡发育、排卵和黄体形成的关键转录因子。 即使给予外源性促性腺激素，Fos缺陷小鼠也不能排卵和形成CL（1）， 提示卵巢Fos表达对正常排卵和黄体化是必需的。不过小 目前还不清楚FOS/AP-1转录因子如何影响卵巢中的这些过程。我们 初步研究首次揭示了FOS的表达在显性表达中高度上调， 从正常月经周期女性中给予hCG后收集的卵泡以及在给予hCG后在排卵前卵泡中收集的卵泡 在小鼠中施用。此外，我们证明FOS调节hCG诱导的细胞增殖， 通过直接结合关键排卵基因的启动子， 基因.基于这些新的发现，我们假设FOS/AP-1在排卵中起重要作用， 人类和小鼠的黄体形成/功能。 Fos基因敲除小鼠表现出多效性表型，出生时生存能力显著丧失。确定 卵巢特异性FOS/AP-1的功能/作用，我们建议建立新的转基因小鼠模型， Fos表达以卵巢细胞特异性方式被消除。这些突变小鼠将用于评估 卵巢表型包括卵泡发育、排卵、黄体发育和生育力，以及 鉴定卵巢细胞中FOS/AP-1的下游靶基因（特异性目标#1）。把这些 从小鼠到人类的研究结果，我们将首先描述所有FOS的时空调控表达 和JUN家族成员在排卵前和整个排卵期获得的排卵卵泡中， 骑自行车的女人FOS/AP-1在人类卵巢中的具体作用也将通过鉴定 FOS/AP-1的下游靶基因，并评估FOS作用的细胞影响（具体目标#2）。 从拟议的研究中获得的信息不仅将促进我们对 成功排卵和黄体化所必需的机制，但也有助于未来 因此，本发明提供了用于转化/临床应用的方法，从而导致体内和体外生育力的改善的管理。

Abstract Understanding the cellular events underlying ovulation and subsequent corpus luteum (CL) formation is critically important because these biological processes provide the foundation of our ability to regulate female fertility. A fundamental cornerstone of the cellular events induced by the preovulatory gonadotropin surge vital for ovulation and CL formation is the expression of specific transcription factors. However, our knowledge of the identity and regulatory actions of gonadotropin-induced key transcription factors remains limited. A recent study has shed light on a member of the activator protein-1 (AP-1) transcription factor family, FOS (a.k.a. c-fos), as a key transcription factor involved in follicular development, ovulation, and luteal formation. Fos-deficient mice failed to ovulate and form CL even when exogenous gonadotropins were administered (1), indicating that the ovarian expression of Fos is necessary for normal ovulation and luteinization. However, little to nothing is known exactly how the FOS/AP-1 transcription factor affects these processes in the ovary. Our preliminary study revealed for the first time that the expression of FOS is highly up-regulated in dominant follicles collected after hCG administration from normally cycling women and in preovulatory follicles after hCG administration in mice. Moreover, we demonstrated that FOS regulated the hCG-induced increase in the expression of key ovulatory genes in human granulosa cells by directly binding to the promoters of these genes. Based on these novel findings, we hypothesized that FOS/AP-1 plays essential roles in ovulation and luteal formation/function both in humans and mice. Fos null mice displayed a pleiotropic phenotype with significant loss of viability at birth. To determine the ovary-specific function/action of FOS/AP-1, we propose to establish novel transgenic mouse models in which Fos expression is ablated in an ovarian cell-specific manner. These mutant mice will be used to assess the ovarian phenotype including follicular development, ovulation, luteal development, and fertility as well as to identify downstream target genes of FOS/AP-1 in ovarian cells (Specific Aim #1). To relate and compare the findings from mice to humans, we will first characterize the spatiotemporally regulated expression of all FOS and JUN family members in ovulatory follicles obtained before and throughout the periovulatory period from normally cycling women. The specific role of FOS/AP-1 in human ovaries will also be determined by identifying downstream target genes of FOS/AP-1 and assessing the cellular impact(s) of FOS' action (Specific Aim #2). The information obtained from the proposed studies will not only advance our understanding of the mechanism necessary for successful ovulation and luteinization but also be instrumental for future translational/clinical application, thus leading to improved management of fertility in vivo and in vitro.