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 非常重要，因为这些生物过程提供了我们调节女性的能力的基础 生育能力。排卵前促性腺激素激增引起的细胞事件的基本基石 对于排卵和CL的形成是特定转录因子的表达。然而，我们所知道的 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 (也就是C-fos)，作为一个关键的转录因子参与卵泡发育、排卵和黄体形成。 FOS基因缺陷小鼠即使注射外源性促性腺激素也不能排卵和形成CL(1)， 提示Fos在卵巢中的表达是正常排卵和黄体形成所必需的。然而，几乎没有 对于FOS/AP-1转录因子如何影响卵巢中的这些过程，我们几乎一无所知。我们的 初步研究首次发现Fos在优势基因中的表达高度上调 正常周期妇女应用hCG后收集的卵泡和hCG后排卵前卵泡 小鼠给药。此外，我们还证明了FOS调节hCG诱导的血管内皮细胞增殖。 与关键排卵基因启动子直接结合在人颗粒细胞中的表达 基因。基于这些新的发现，我们假设Fos/AP-1在排卵和 人和小鼠的黄体形成/功能。 Fos基因缺失的小鼠在出生时表现出多效性表型，并显著丧失了生存能力。要确定 Fos/AP-1的卵巢特异性功能/作用，我们建议建立新的转基因小鼠模型。 Fos的表达以卵巢细胞特异性的方式被消融。这些突变小鼠将被用来评估 卵巢表型包括卵泡发育、排卵、黄体发育和生育，以及 确定卵巢细胞Fos/AP-1下游靶基因(特异性目标1)。来联系和比较 从小鼠到人类的研究结果，我们将首先表征所有fos的时空调控表达 和Jun家族成员在排卵期前和整个排卵期从 通常是骑自行车的女人。Fos/AP-1在人类卵巢中的具体作用也将通过识别 Fos/AP-1下游靶基因和评估FOS作用的细胞影响(特异靶2)(S) 从建议的研究中获得的资料，不单会加深我们对 成功排卵和黄体生成所必需的机制，但对未来也是有用的 翻译/临床应用，从而改善体内和体外生育力的管理。

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.