SIRT1 facilitates primordial follicle recruitment independent of deacetylase activity through directly modulating Akt1 and mTOR transcription

In female mammals, the majority of primordial follicles (PFs) are physiologically quiescent while only a few of them are activated and enter the growing follicle pool. Specific molecules such as mTOR and AKT have been proven to be important for PFs activation. However, how the transcription of these genes is regulated is not clear. The activators of mTOR or AKT were successfully used to rescue the fertility of patients with premature ovarian insufficiency. The low efficiency and uncertain safety of the drugs used hinder the clinical use of in vitro activation (IVA) of PFs.

        Here, SIRT1, an NAD-dependent deacetylase, was demonstrated to activate mice PF independent of its deacetylase activity. SIRT1 was prominently expressed in pregranulosa cells and oocytes and increased during PFs activation. PFs activation was achieved by up-regulation of SIRT1 with specific activator or overexpression of SIRT1. Morever, knockdown of SIRT1 in oocytes or pregranulosa cells could significantly suppresses PF activation. Further studies demonstrated that SIRT1 enhanced both Akt1 and mTOR expression by acting more as a transcription co-factor, directly binding to the respective gene promoters, than a deacetylase. Importantly, we performed potential clinical applications and results showed that short-term resveratrol treatment successfully awake the PFs of mouse and human. Resveratrol induced IVA could be a candidate strategy to develop more efficient procedures for future clinical use.

Working model for the role of SIRT1 during PF initial recruitment

(A) The systematically changed molecules together promote the activation of PFs in the mouse ovary. In pGCs, SIRT1 directly binds to the promoters of either mTOR to facilitate transcription, which mediates their transformation from pregranulosa cells to granulosa cells. In oocytes, SIRT1 upregulates the transcription of both mTOR and Akt1 by the same means as in the pGCs. (B) Transient RSV treatment could awake the dormant huaman and mouse PFs.

 SIRT1 facilitates primordial follicle recruitment independent of deacetylase activity through directly modulating Akt1 and mTOR transcription.pdf