ROLE OF SF1 AND DAX1 IN OVARIAN FUNCTION

SF1 和 DAX1 在卵巢功能中的作用

• 批准号: 6410468
• 负责人: James Larry JAMESON
• 金额: $ 17.7万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-15 至 2001-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6410468
• 关键词: biological signal transduction; cAMP response element binding protein; cyclic AMP; developmental genetics; embryonic stem cell; estrus; female; follicle stimulating hormone; gel mobility shift assay; gene expression; gene targeting; genetic promoter element; genetic regulatory element; genetic transcription; genetically modified animals; histogenesis; hormone regulation /control mechanism; in situ hybridization; inhibin; laboratory mouse; ovary; protein protein interaction; site directed mutagenesis; transcription factor; western blottings

FSH, acting primarily through the protein kinase A pathway, regulates follicular development and function. Recent studies reveal convergence of the FSH/cAMP pathway with a group of transcription factors (SF-1, DAX-1) that control target genes in the ovary. SF-1 and DAX-1 are orphan nuclear receptors that play a key role in the development and function of the adrenal, gonads, and pituitary gonadotropes. A gene knock-out of SF-1 prevents the development of these organs, and SF-1 response elements have been identified in promoters of many different ovarian genes. Mutation of the X-linked DAX-1 gene causes the syndrome of adrenal hypoplasia congenital. It is characterized by the absence of the adult zone of the adrenal cortex with hypogonadotropic hypogonadism with apparently normal testicular Leydig cell function. Duplication of DAX-1 causes sex reversal in genetic males, and DAX-1 has been postulated to foster ovarian development. We have shown that DAX-1 modulates SF-1 action and play a critical role in ovarian development and function. We have shown that DAX- 1 modulates SF-1 action and hypothesize that the balance of DAX-1 and SF-1 expression in the ovary regulates its development, and subsequently, the function of various target genes like inhibin-alpha and steroidogenic enzyme genes. We propose an integrated group of in vitro and in vivo studies to further define the functions of SF-1 and DAX-1 in the ovary. There are three specific aims: 1) To examine mechanisms by which the cAMP and SF-1 pathways interact to regulate ovarian genes. We hypothesize that transcriptional co-factors, such as CBP, provide a basis for convergence of the FSH signaling pathway with the nuclear receptor, SF-1; 2) To determine the basis of divergent effects of DAX-1 on SF-1-mediated transcription of different ovarian target genes. We hypothesize that DAX-1 promoters will be studied as representative examples of SF-1 responsive genes that are regulated differentially by DAX-1; 3) To determine the effect of targeted deletion and over-expression of DAX-1 on ovarian gene expression. These studies will test in vivo whether DAX-1 plays a role in ovarian development and in the regulation of ovarian gene expression.

FSH主要通过蛋白激酶A途径发挥作用，调节 卵泡发育和功能。最近的研究表明， FSH/cAMP途径与一组转录因子(SF-1、DAX-1) 它控制着卵巢中的目标基因。SF-1和DAX-1是孤儿核 在细胞的发育和功能中起关键作用的受体 肾上腺、性腺和垂体促性腺激素。SF-1的一种基因敲除 阻止这些器官的发育，而SF-1反应元件 在许多不同卵巢基因的启动子中都被发现。基因突变 X连锁DAX-1基因导致肾上腺发育不全综合征 先天的。它的特点是没有成人区。 肾上腺皮质促性腺激素减退症明显正常 睾丸间质细胞功能。DAX-1基因重复导致性反转 在遗传男性中，DAX-1被假设为促进卵巢 发展。我们已经证明，DAX-1调节SF-1的作用并发挥作用 在卵巢发育和功能中的关键作用。我们已经证明了DAX- 1调节SF-1的作用，并假设DAX-1和SF-1的平衡 卵巢中的表达调节其发育，随后， 抑制素-α和类固醇合成等靶基因的功能 酶基因。我们提出了一个完整的体外和体内研究小组 进一步明确SF-1和DAX-1在卵巢中的功能。 有三个具体目标：1)审查营地 而SF-1通路相互作用，调节卵巢基因。我们假设 转录辅助因子，如CBP，提供了趋同的基础 FSH信号通路与核受体SF-1的关系；2) 确定DAX-1对SF-1介导的分化作用的基础 不同卵巢靶基因的转录。我们假设DAX-1 启动子将作为SF-1反应的代表性例子进行研究 受DAX-1差异调控的基因；3)确定 DAX-1基因的靶向缺失和过表达对卵巢基因的影响 表情。这些研究将在体内测试DAX-1是否在 卵巢发育和卵巢基因表达的调控。