CELLULAR SIGNALS IN OVULATION AND LUTEINIZATION

促黄体生成激素（LH）激增启动两个过程独特的 脊椎动物卵巢排卵和黄体化。两者都需要表达式 和特定核受体的激活。孕激素受体 和SF-1（类固醇生成因子-1）。LH诱导快速但短暂的 PR mRNA和蛋白（A和B亚型）在分化型乳腺癌中的表达 大鼠排卵前卵泡的颗粒细胞。定向破坏 PR基因（PRKO）产生的小鼠不排卵，从而证实了 PR和颗粒细胞在启动事件中的关键作用， 排卵LH诱导颗粒细胞PR的分子基础 仍然难以捉摸，但似乎涉及机制以外或此外 雌二醇受体（ER）的激活。的可用性 小鼠PR启动子和PR缺陷小鼠为我们提供了独特的 有机会扩展我们对PR激素调节的研究， 确定PR在排卵生理学中的功能作用。这 将通过1）分析小鼠PR启动子-报告基因构建体 转染到颗粒细胞中，2）使用PRKO小鼠模型，和 野生型小鼠鉴定和分析LH和Pr调节的诱导 3）将这些基因产物的功能与 特异性蛋白酶和激肽的活性和定位可能 与排卵过程有关。排卵前LH激增 启动颗粒细胞的完全分子重编程， 终末分化及黄体细胞表达 特定基因我们的特定基因，α 2-巨球蛋白是由 至少有两种不同的信号通路其中包括孤儿成员， 核受体超家族SF-1和COUP-TF（鸡卵清蛋白 上游刺激转录因子）以及至少一个成员 一类新的转录因子（信号转导和 转录激活因子或Stats），即Stat 5 b。而 SF-1（COUP-TF？）功能可由卵巢中的促性腺激素调节 细胞中，Stat 5 b被PRL激活。因此，我们在独特的 能够确定Stat 5 b如何与孤儿相互作用 核受体来调节α 2 M的表达。这些模型将 使我们能够确定LH如何调节诱导（PR）和激活 （SF-1）的核转录因子，以及这些因子如何反过来 介导LH刺激排卵和黄体化-两个主要事件， 哺乳动物的卵巢决定生育能力。

The luteinizing hormone (LH) surge initiates two processes unique to the vertebrate ovary-ovulation and luteinization. Both require the expression and activation of specific nuclear receptors. PR (progesterone receptor) and SF-1 (steroidogenic factor-1). LH induces the rapid but transient expression of PR mRNA and protein (A and B isoforms) in differentiated granulosa cells of rat preovulatory follicles. Targeted disruption of the PR gene (PRKO) generated mice that do not ovulate, thereby confirming the critical role of PR and granulosa cells in initiating events that control ovulation. The molecular basis by which LH induces PR in granulosa cells remain elusive but appears to involve mechanisms other than or in addition to activation of the estradiol receptor (ER). The availability of the mouse PR promoter and mice deficient in PR provides us with the unique opportunity to extend our studies on the hormonal regulation of PR and to determine the functional roles of PR in the physiology of ovulation. This will be accomplished by 1) analyzing mouse PR promoter-reporter constructs transfected into granulosa cells, 2) using the PRKO mouse model and wildtype mice to identify and analyze the induction of LH and Pr regulated genes and 3) relating the function of these gene products to the activities and localization of specific proteases and kinins likely associated with the ovulatory process. Prior to ovulation, the LH surge initiates the complete molecular reprogramming of granulosa cells leading to their terminal differentiation and the expression of luteal cell specific genes. Our specific genes, alpha2-macroglobulin is regulated by at least two distinct signaling pathways. These include orphan members of the nuclear receptor superfamily, SF-1 and COUP-TFs (chick ovalbumin upstream stimulatory-transcription factors) as well as at least one member of a novel class of transcription factors (signal transducers and activators of transcription or Stats), namely Stat 5b. Whereas the function of SF-1 (COUP-TFs?) can be regulated by gonadotropins in ovarian cells, Stat 5b is activated by PRL. Therefore, we are in the unique position of being able to determine how Stat 5b interacts with orphan nuclear receptors to regulate the expression of alpha2M. These models will allow us to determine how LH regulates the induction (PR) and activation (SF-1) of nuclear transcription factors and how these factors in turn mediate LH stimulation of ovulation and luteinization-two major events in the mammalian ovary that acutely determine fertility.