HDAC6 regulates primordial follicle activation through mTOR signaling pathway

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.

Enhanced glycolysis in granulosa cells promotes the activation of primordial follicles through mTOR signaling

“…This energy shortage activates AMPK to increase catabolism, especially glycolysis [ 20 ], and enhanced glycolysis triggers the inhibition of AMPK and the subsequent activation of mTOR in the mouse brain [ 30 ]. In this study, the standard medium for culturing ovarian tissues contains pyruvate [ 10 – 12 ]. Short-term pyruvate deprivation promotes glycolysis via negative feedback of AMPK, and then enhanced glycolysis subsequently activates mTOR signaling by decreasing AMPK activity in mouse ovaries.…”

“…The inhibition of oocyte growth is lifted, and the follicle begins to grow. Other molecules have also been reported to be involved in the activation of primordial follicles by regulating the above signaling pathways, including mitogen-activated protein kinase (MAPK3/1), E-cadherin, and histone deacetylase 6 (HDAC6) [ 10 – 12 ].…”

Effects and potential mechanism of Ca2+/calmodulin‑dependent protein kinase II pathway inhibitor KN93 on the development of ovarian follicle

“…After the formation of the final primordial follicles pool, the periodic activation of primordial follicles will continuously deplete the number of primordial follicles, shortening the reproductive lifespan. Therefore, adequately regulating the speed of primordial follicle activation will prolong the reproductive life of the ovaries (5). A number of studies have previously reported that KN93 is a specific inhibitor of CaMKII that can regulate various physiological and pathological processes by specifically inhibiting CaMKII activity (20,21).…”

“…According to the previously reported morphological and functional changes that occur during follicular development, follicles can be divided into primordial, primary, secondary and mature follicles (2)(3)(4). In particular, formation and activation of primordial follicles is key for determining reproductive ability (5). In the majority of mammalian species, the formation of primordial follicles typically occurs during the embryonic stages or around birth (6)(7)(8).…”

An Interplay between Epigenetics and Translation in Oocyte Maturation and Embryo Development: Assisted Reproduction Perspective

“…Recently, primordial follicle activation by mTOR signalling was associated with decreased HDAC6 activity. This finding may be of importance for the management of premature ovarian failure (POF) as an alternative approach to primordial follicle in vitro activation (IVA) [ 48 ]. HDAC8 has a similarly indispensable role as HDAC6 and is located on spindle poles.…”