Rictor/mTORC2 Pathway in Oocytes Regulates Folliculogenesis, and Its Inactivation Causes Premature Ovarian Failure
Rictor/mTORC2 Pathway in Oocytes Regulates Folliculogenesis, and Its Inactivation Causes Premature Ovarian Failure
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卵母细胞中的 Rictor/mTORC2 通路调节卵泡发生，其失活导致卵巢早衰
DOI：
10.1074/jbc.m114.605261
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发表时间：
2015-03-06
影响因子：
4.8
通讯作者：
Bai, Xiaochun
中科院分区：
文献类型：
--
作者：
Chen, Zhenguo;Kang, Xiangjin;Bai, Xiaochun
卵巢卵泡发生的分子基础和卵巢早衰（POF）的发病机制尚未完全了解，POF是女性不孕的常见原因。雷帕霉素复合物2（mTORC 2）的机制靶标正在成为细胞代谢、增殖和存活的中心调节剂。然而，其在卵泡发生和POF中的作用尚未报道。在这里，我们发现mTORC 2的信号传导活性在4-乙烯基环己烯二环氧化物（VCD）诱导的POE小鼠模型中受到抑制。值得注意的是，卵母细胞特异性切除Rector（mTORC 2的关键组分）的小鼠表现出POF表型，包括大量卵泡死亡、功能性卵泡过度丧失、性腺激素分泌异常，以及因此在条件性基因敲除（cKO）小鼠中继发性生育力低下。此外，在cKO小鼠中观察到Ser-473-磷酸化Akt和Ser-253-磷酸化Foxo 3a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，在4-VCD处理的卵巢中复制了信号传导改变。这些结果表明Rictor/mTORC 2/Akt/Foxo 3a促存活信号传导轴在卵泡发生中的关键作用。有趣的是，母体Rictor的丢失并没有导致cKO小鼠胚胎或胎盘的明显发育缺陷，这表明母体Rictor对于植入前胚胎发育是不利的。我们的研究结果共同表明Rictor/mTORC 2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基因敲除小鼠作为POF新模型的实用性。
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 POE mouse model. Notably, mice with oocyte-specific ablation of Rector, 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.