title: Rictor/mTORC2 pathway in oocytes regulates folliculogenesis, and its inactivation causes premature ovarian failure.
abstract: Molecular basis of ovarian folliculogenesis and etiopathogenesis of premature ovarian failure (POF), a common cause of infertility in women, are not fully understood. Mechanistic target of rapamycin complex 2 (mTORC2) is emerging as a central regulator of cell metabolism, proliferation, and survival. However, its role in folliculogenesis and POF has not been reported. Here, we showed that the signaling activity of mTORC2 is inhibited in a 4-vinylcyclohexene diepoxide (VCD)-induced POF mouse model. Notably, mice with oocyte-specific ablation of Rictor, a key component of mTORC2, demonstrated POF phenotypes, including massive follicular death, excessive loss of functional ovarian follicles, abnormal gonadal hormone secretion, and consequently, secondary subfertility in conditional knock-out (cKO) mice. Furthermore, reduced levels of Ser-473-phosphorylated Akt and Ser-253-phosphorylated Foxo3a and elevated pro-apoptotic proteins, Bad, Bax, and cleaved poly ADP-ribose polymerase (PARP), were observed in cKO mice, replicating the signaling alterations in 4-VCD-treated ovaries. These results indicate a critical role of the Rictor/mTORC2/Akt/Foxo3a pro-survival signaling axis in folliculogenesis. Interestingly, loss of maternal Rictor did not cause obvious developmental defects in embryos or placentas from cKO mice, suggesting that maternal Rictor is dispensable for preimplantation embryonic development. Our results collectively indicate key roles of Rictor/mTORC2 in folliculogenesis, follicle survival, and female fertility and support the utility of oocyte-specific Rictor knock-out mice as a novel model for POF.
authors.affiliation: From the State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: the Center for Reproductive Medicine, Third Affiliated Hospital of Guangzhou Medical University, Key Laboratory for Reproductive Medicine of Guangdong Province, Key Laboratory for Major Obstetric Diseases of Guangdong Province, and Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou 510150, and.
authors.forename: Xiangjin
authors.initials: X
authors.lastname: Kang
authors.affiliation: the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, and.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515.
authors.forename: Heling
authors.initials: H
authors.lastname: Dong
authors.affiliation: From the State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515.
authors.forename: Caixia
authors.initials: C
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: From the State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515.
authors.forename: Wanlu
authors.initials: W
authors.lastname: Zhao
authors.affiliation: From the State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Jia
authors.affiliation: From the State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: the Center for Reproductive Medicine, Third Affiliated Hospital of Guangzhou Medical University, Key Laboratory for Reproductive Medicine of Guangdong Province, Key Laboratory for Major Obstetric Diseases of Guangdong Province, and Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou 510150, and.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: the State Key Laboratory of Experimental Hematology, Institute of Hematology, Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.affiliation: the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, and.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhong
authors.affiliation: the Center for Reproductive Medicine, Third Affiliated Hospital of Guangzhou Medical University, Key Laboratory for Reproductive Medicine of Guangdong Province, Key Laboratory for Major Obstetric Diseases of Guangdong Province, and Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou 510150, and dhz_gz@hotmail.com.
authors.forename: Hongzi
authors.initials: H
authors.lastname: Du
authors.affiliation: From the State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, baixc15@smu.edu.cn.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000235:genetics*; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D006080:Ovarian Follicle / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D016649:Primary Ovarian Insufficiency / Q000235:genetics / Q000473:pathology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; C546843:mTOR protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: Apoptosis; Follicle Survival; Folliculogenesis; Gene Knockout; Mammalian Target of Rapamycin (mTOR); Oocyte; Oogenesis; Ovary; Premature Ovarian Failure; Rictor; mTORC2