Chen Zhenguo, Kang Xiangjin, Wang Liping, Dong Heling, Wang Caixia, Xiong Zhi, Zhao Wanlu, Jia Chunhong, Lin Jun, Zhang Wen, Yuan Weiping, Zhong Mei, Du Hongzi, Bai Xiaochun
From the State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515.
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.
J Biol Chem. 2015 Mar 6;290(10):6387-96. doi: 10.1074/jbc.M114.605261. Epub 2015 Jan 6.
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.
卵巢卵泡发生的分子基础以及女性不育的常见原因——卵巢早衰（POF）的发病机制尚未完全明确。雷帕霉素复合物2（mTORC2）的机制靶点正逐渐成为细胞代谢、增殖和存活的核心调节因子。然而，其在卵泡发生和POF中的作用尚未见报道。在此，我们发现mTORC2的信号活性在4-乙烯基环己烯二环氧化物（VCD）诱导的POF小鼠模型中受到抑制。值得注意的是，卵母细胞特异性敲除mTORC2的关键组分Rictor的小鼠表现出POF表型，包括大量卵泡死亡、功能性卵巢卵泡过度丢失、性腺激素分泌异常，以及条件性敲除（cKO）小鼠继发性生育力低下。此外，在cKO小鼠中观察到Ser-473磷酸化的Akt和Ser-253磷酸化的Foxo3a水平降低，促凋亡蛋白Bad、Bax和裂解的聚ADP核糖聚合酶（PARP）水平升高，这重现了4-VCD处理的卵巢中的信号改变。这些结果表明Rictor/mTORC2/Akt/Foxo3a促存活信号轴在卵泡发生中起关键作用。有趣的是，母本Rictor的缺失并未在cKO小鼠的胚胎或胎盘中引起明显的发育缺陷，这表明母本Rictor对于植入前胚胎发育是可有可无的。我们的结果共同表明Rictor/mTORC2在卵泡发生、卵泡存活和女性生育力中的关键作用，并支持卵母细胞特异性Rictor敲除小鼠作为POF新模型的实用性。
