IRXB Factors Direct Follicle Maturation

描述（由申请人提供）：在卵巢发育过程中，生殖细胞囊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、成熟和排卵后的最终释放提供了框架。我们的长期工作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-体细胞通讯的途径和因素。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以最终保护遗传转移和物种生存至关重要。 指导这一建议的基本假设是，易洛魁人同源框转录因子Irx 3/5，这是由连环蛋白密切调控，协调体细胞卵母细胞通讯，以促进卵母细胞存活和卵泡成熟的早期阶段。在AIM 1中，诱导型小鼠模型将用于敲除和敲入性腺Irx 3/5活性，以鉴定其时间和空间表达的关键时刻，所述时间和空间表达调节生殖系囊肿和原始卵泡中体细胞与卵母细胞之间的通信，以促进卵母细胞健康和存活。然后，在AIM 2中，我们将通过评估Irx 3表达的重新引入是否可以拯救连环蛋白突变卵巢中的生殖细胞死亡表型，研究体细胞和生殖细胞中连环蛋白对Irx 3/5的时空转录调控以及该途径的功能结果。这些目标的成功完成将揭示一种新的途径，连环蛋白-Irx 3/5，在控制卵母细胞-颗粒细胞通讯，其中断可能有助于不孕症和卵巢早衰的原因。

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.