Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, College of Life Science, Ningxia University, 750021, Yinchuan, China.
Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, 550009, Guiyang, Guizhou, China.
Cell Death Dis. 2021 May 29;12(6):559. doi: 10.1038/s41419-021-03842-1.
Primordial follicle pool established perinatally is a non-renewable resource which determines the female fecundity in mammals. While the majority of primordial follicles in the primordial follicle pool maintain dormant state, only a few of them are activated into growing follicles in adults in each cycle. Excessive activation of the primordial follicles accelerates follicle pool consumption and leads to premature ovarian failure. Although previous studies including ours have emphasized the importance of keeping the balance between primordial follicle activation and dormancy via molecules within the primordial follicles, such as TGF-β, E-Cadherin, mTOR, and AKT through different mechanisms, the homeostasis regulatory mechanisms of primordial follicle activation remain unclear. Here, we reported that HDAC6 acts as a key negative regulator of mTOR in dormant primordial follicles. In the cytoplasm of both oocytes and granulosa cells of primordial follicles, HDAC6 expressed strong, however in those activated primordial follicles, its expression level is relatively weaker. Inhibition or knockdown of HDAC6 significantly promoted the activation of limited primordial follicles while the size of follicle pool was not affected profoundly in vitro. Importantly, the expression level of mTOR in the follicle and the activity of PI3K in the oocyte of the follicle were simultaneously up-regulated after inhibiting of HDAC6. The up-regulated mTOR leads to not only the growth and differentiation of primordial follicles granulosa cells (pfGCs) into granulosa cells (GCs), but the increased secretion of KITL in these somatic cells. As a result, inhibition of HDAC6 awaked the dormant primordial follicles of mice in vitro. In conclusion, HDAC6 may play an indispensable role in balancing the maintenance and activation of primordial follicles through mTOR signaling in mice. These findings shed new lights on uncovering the epigenetic factors involved physiology of sustaining female reproduction.
原始卵泡库在围生期建立，是哺乳动物女性生育力的不可再生资源。虽然原始卵泡库中的大多数原始卵泡处于休眠状态，但在每个周期中，只有少数原始卵泡在成年后被激活为生长卵泡。原始卵泡的过度激活会加速卵泡库的消耗，导致卵巢早衰。尽管包括我们在内的先前研究强调了通过原始卵泡内的分子（如 TGF-β、E-Cadherin、mTOR 和 AKT）通过不同的机制来维持原始卵泡激活和休眠之间的平衡的重要性，但原始卵泡激活的体内平衡调节机制仍不清楚。在这里，我们报道了 HDAC6 作为休眠原始卵泡中 mTOR 的关键负调控因子。在原始卵泡的卵母细胞和颗粒细胞的细胞质中，HDAC6 表达强烈，然而在那些被激活的原始卵泡中，其表达水平相对较弱。HDAC6 的抑制或敲低显著促进了有限的原始卵泡的激活，而体外卵泡库的大小没有受到明显影响。重要的是，抑制 HDAC6 后，卵泡中 mTOR 的表达水平和卵泡中卵母细胞的 PI3K 活性同时上调。上调的 mTOR 不仅导致原始卵泡颗粒细胞 (pfGCs) 生长和分化为颗粒细胞 (GCs)，而且这些体细胞中 KITL 的分泌增加。结果，HDAC6 的抑制在体外唤醒了小鼠的休眠原始卵泡。总之，HDAC6 可能通过 mTOR 信号通路在小鼠中在维持和激活原始卵泡方面发挥不可或缺的作用。这些发现为揭示参与女性生殖维持的表观遗传因素提供了新的线索。
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