IRXB Factors Direct Follicle Maturation

描述(由申请人提供)：在卵巢发育过程中，胚系囊泡和原始卵泡内的体细胞和卵母细胞之间建立的基本关系为卵母细胞的成功存活、成熟和排卵时的最终释放提供了框架。我们工作的一个长期目标是发现在卵巢发育和早期卵泡形成过程中促进卵母细胞和体细胞交流的途径和因素。这个问题对于我们开发在卵泡发育和成熟过程中培养卵母细胞健康的方法，最终保护遗传转移和物种生存至关重要。支持这一建议的基本假设是易洛魁同源盒转录因子IRX3/5受连接素的严格调控，协调体细胞-卵母细胞之间的通讯，促进卵母细胞存活和卵泡成熟的早期阶段。在AIM 1中，将使用可诱导的小鼠模型来敲除和敲入性腺IRX3/5的活性，以确定其时空表达的关键点，该临界点调节生殖细胞和原始卵泡中体细胞和卵母细胞之间的通讯，以促进卵母细胞的健康和存活。然后，在AIM 2中，我们将通过评估重新引入IRX3表达是否可以挽救连接素突变卵巢的生殖细胞死亡表型，来研究连环蛋白在体细胞和生殖细胞中对IRX3/5的时空转录调控以及这一途径的功能结果。这些目标的成功完成将揭示一条新的途径，即连环蛋白-IRX3/5，在控制卵母细胞-颗粒细胞通讯方面，该途径的中断可能导致不孕不育和卵巢早衰。

DESCRIPTION (provided by applicant): The fundamental relationships established between somatic cells and oocytes within germline cysts and primordial follicles during ovary development provide the framework for successful oocyte survival, maturation, and ultimate release upon ovulation. A long-term goal of our work is to discover the pathways and factors that facilitate oocyte-somatic cell communication during ovary development and early follicle formation. This issue is critical for us to develop the means to cultivate oocyte health during follicle development and maturation to ultimately preserve genetic transfer and species survival. The fundamental hypothesis guiding this proposal is that Iroquois homeobox transcription factors, Irx3/5, which are tightly regulated by ¿catenin, coordinate somatic cell-oocyte communication to promote oocyte survival and early stages of follicle maturation. In AIM 1, inducible mouse models will be used to knockout and knock-in gonad Irx3/5 activity to identify their critical juncture of temporal and spatial expression that regulates communication between somatic cells and the oocyte in germline cysts and primordial follicles to promote oocyte health and survival. Then in AIM 2, we will investigate the temporal and spatial transcriptional regulation of Irx3/5 by ¿catenin in somatic and germ cells and the functional outcome of this pathway by evaluating whether re-introduction of Irx3 expression can rescue the germ cell death phenotype in ¿catenin-mutant ovaries. Successful completion of these aims will uncover a novel pathway, ¿catenin-Irx3/5, in the control of oocyte-granulosa cell communication whose disruption may contribute to causes of infertility and premature ovarian failure.