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Here, we report that Yes\u2010Associated 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\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo. Foxl2<\/jats:italic>\n                    promoter\u2013driven knockout of\n                    <jats:italic>Yap1<\/jats:italic>\n                    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,\n                    <jats:italic>Cyp19a1<\/jats:italic>\n                    promoter\u2013driven knockout of\n                    <jats:italic>Yap1<\/jats:italic>\n                    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\u2010\u03b2 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.\u2014Lv, 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\u201310064 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201900179rr","type":"journal-article","created":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T16:49:41Z","timestamp":1560530981000},"page":"10049-10064","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":116,"title":["Timely expression and activation of YAP1 in granulosa cells is essential for ovarian follicle development"],"prefix":"10.1096","volume":"33","author":[{"given":"Xiangmin","family":"Lv","sequence":"first","affiliation":[{"name":"Vincent Center for Reproductive Biology Department of Obstetrics and Gynecology Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Department of Obstetrics and Gynecology Olson Center for Women's Health University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbo","family":"He","sequence":"additional","affiliation":[{"name":"Vincent Center for Reproductive Biology Department of Obstetrics and Gynecology Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Department of Obstetrics and Gynecology Olson Center for Women's Health University of Nebraska Medical Center  Omaha Nebraska USA"},{"name":"College of Animal Sciences and Veterinary Medicine Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Huang","sequence":"additional","affiliation":[{"name":"Vincent Center for Reproductive Biology Department of Obstetrics and Gynecology Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbo","family":"Wang","sequence":"additional","affiliation":[{"name":"Vincent Center for Reproductive Biology Department of Obstetrics and Gynecology Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Guangdong Province Key Laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohua","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Olson Center for Women's Health University of Nebraska Medical Center  Omaha Nebraska USA"},{"name":"College of Animal Sciences and Veterinary Medicine Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Olson Center for Women's Health University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Olson Center for Women's Health University of Nebraska Medical Center  Omaha Nebraska USA"},{"name":"Department of Obstetrics and Gynecology The Eighth Affiliated Hospital of Sun Yat\u2010Sen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingcheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Fred and Pamela Buffett Cancer Center University of Nebraska Medical Center  Omaha Nebraska USA"},{"name":"Department of Pathology and Microbiology University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Olson Center for Women's Health University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara K.","family":"Timm","sequence":"additional","affiliation":[{"name":"Heartland Center for Reproductive Medicine, PC  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Maclin","sequence":"additional","affiliation":[{"name":"Heartland Center for Reproductive Medicine, PC  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jixin","family":"Dong","sequence":"additional","affiliation":[{"name":"Fred and Pamela Buffett Cancer Center University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo. 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