Abstract
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.
Highlights
Ovarian follicles are the basic and non-renewable reproductive unit of female mammals[1,2]
We found that the signal of HDAC6 was homogenous stronger in the majority of primordial follicles, but was relatively weaker in some primordial follicles, which may be on the way to be activated
The statistics results show that 3.5 ± 0.2% of primordial follicles with weaker HDAC6 expression are presented in adult ovaries, while 4 ± 0.4% of primordial follicles with weaker HDAC6 expression are presented in 5 dpp ovaries (Fig. S3)
Summary
Ovarian follicles are the basic and non-renewable reproductive unit of female mammals[1,2]. The majority of follicles reserved are primordial follicles, which are maintained at dormant or quiescent. Zhang et al Cell Death and Disease (2021)12:559 activation and dormant of primordial follicles is still obscure. The activation of primordial follicle is a complex and coordinated process among individual oocyte, pfGCs, and even the surrounding micro-environment[14]. Many molecules mentioned above are involved in the activation process of primordial follicle originated from the pfGCs, of which mTORC1 signaling in pfGCs and PI3K signaling in oocytes is the dominant pathway[15]
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