Timely expression and activation of YAP1 in granulosa cells is essential for ovarian follicle development

Abstract

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 in vitro and in vivo. Foxl2 promoter–driven knockout of Yap1 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, Cyp19a1 promoter–driven knockout of Yap1 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. FASEB J. 33, 10049–10064 (2019). http://www.fasebj.org

Newly Identified Regulators of Ovarian Folliculogenesis and Ovulation

“…The reciprocal effect, manifested by a reduced number of primordial follicles and elevation in secondary follicles, is obtained upon YAP1 overexpression [ 47 , 52 ]. These findings are supported by another study, in which a specific deletion of YAP1 in GCs of primordial follicles resulted in subfertility which was subsequent to increased cell apoptosis, reduced number of CL and a decline in ovarian size [ 48 ]. Taken together these studies suggest that YAP1 mainly induces the transition of follicles from the primordial to the primary stage.…”

“…The phosphorylated YAP1 and WWTR1 are sequestered to the cytoplasm, and their action as transcriptional co-activators is prevented [ 45 , 46 ]. In the ovaries, YAP1 is localized in the cytoplasm of GC of primordial and secondary follicles [ 47 , 48 ]. Follicular development in the ovary is accompanied by a reduction in MST1 and LATS2 and elevation in YAP1 expression, accompanied by a decrease in MST1 phosphorylation, indicating its inactivation [ 47 ].…”

“…As mentioned previously, YAP1 is involved in ovarian follicles development [ 47 , 48 , 52 ]. Consistent with oocyte-induced YAP1 activation in cultured GCs, YAP1 is localized to both, the nucleus and the cytoplasm, whereas, in co-cultures of GCs and oocytes YAP1 is mainly nuclear [ 100 ].…”

LncRNA NNT‐AS1 promotes non‐small cell lung cancer progression through regulating miR‐22‐3p/YAP1 axis

“…In addition, Yes-associated protein (YAP1) is the main effector of the Hippo pathway and contributes to the development of many cancers. 21 EMT exerts a crucial role in tumor metastasis. 22 Activation of the extracellular signal-regulated kinase (ERK) signaling pathway contributes to EMT in lung cancer.…”

“…In addition, Yes‐associated protein (YAP1) is the main effector of the Hippo pathway and contributes to the development of many cancers . EMT exerts a crucial role in tumor metastasis .…”