Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts, USA.
Department of Obstetrics and Gynecology, Olson Center for Women's Health, University of Nebraska Medical Center, Omaha, Nebraska, USA.
FASEB J. 2019 Sep;33(9):10049-10064. doi: 10.1096/fj.201900179RR. Epub 2019 Jun 14.
Although the role of the Hippo signaling pathway in development and tumorigenesis has been extensively studied in multiple organs, its role in ovarian follicle development remains largely unknown. Here, we report that Yes-Associated Protein 1 (YAP1), the major effector of Hippo signaling, is spatiotemporally expressed in ovarian granulosa cells and plays a critical role in the regulation of follicle development. We found that the active form of YAP1 (nuclear YAP1) was predominantly expressed in proliferative granulosa cells, whereas the inactive form of YAP1 (cytoplasmic YAP1) was mainly detected in luteal cells (terminally differentiated granulosa cells). Pharmacological inhibition of YAP1 activity disrupted mouse ovarian follicle development and . promoter-driven knockout of in ovarian granulosa cells resulted in increased apoptosis of granulosa cells, decreased number of corpora lutea, reduced ovarian size, and subfertility in transgenic mice. However, promoter-driven knockout of in differentiated granulosa cells of preovulatory follicles and luteal cells of corpora lutea had no effect on ovarian morphology and fertility. Mechanistic studies demonstrated that YAP1 interacted with epidermal growth factor receptor and TGF-β signaling pathways to regulate granulosa cell proliferation, differentiation, and survival. Results from this study identify YAP1 as a critical regulator of granulosa cell proliferation and differentiation. Balanced expression and activation of YAP1 is essential for follicle development and successful reproduction. YAP1 is a promising target for treatment of subfertility associated with abnormal granulosa cell function.-Lv, X., He, C., Huang, C., Wang, H., Hua, G., Wang, Z., Zhou, J., Chen, X., Ma, B., Timm, B. K., Maclin, V., Dong, J., Rueda, B. R., Davis, J. S., Wang, C. Timely expression and activation of YAP1 in granulosa cells is essential for ovarian follicle development.
尽管 Hippo 信号通路在多个器官的发育和肿瘤发生中的作用已经得到了广泛研究，但它在卵巢卵泡发育中的作用在很大程度上仍然未知。在这里，我们报告说 Yes 相关蛋白 1（YAP1），Hippo 信号的主要效应物，在卵巢颗粒细胞中时空表达，并在卵泡发育的调节中发挥关键作用。我们发现，YAP1 的活性形式（核 YAP1）主要表达在增殖性颗粒细胞中，而 YAP1 的非活性形式（细胞质 YAP1）主要在黄体细胞（终末分化的颗粒细胞）中检测到。YAP1 活性的药理学抑制破坏了小鼠卵巢卵泡发育，并且，在卵巢颗粒细胞中启动子驱动的 缺失导致颗粒细胞凋亡增加、黄体数量减少、卵巢体积减小和转基因小鼠的生育力降低。然而，在预排卵卵泡的分化颗粒细胞和黄体细胞中启动子驱动的 缺失对卵巢形态和生育力没有影响。机制研究表明，YAP1 与表皮生长因子受体和 TGF-β 信号通路相互作用，调节颗粒细胞增殖、分化和存活。这项研究的结果表明，YAP1 是颗粒细胞增殖和分化的关键调节剂。YAP1 的平衡表达和激活对于卵泡发育和成功繁殖至关重要。YAP1 是治疗与异常颗粒细胞功能相关的生育力低下的有前途的靶标。
