Restricting The Induction Of NGF In Ovarian Stroma Engenders Selective Follicular Activation Through The MTOR Signaling Pathway

In mammalian ovaries,primordial follicles represent the follicular reserve and are the source of all developing follicles.To preserve the primordial follicles not exhausted earlier in the reproductive life,it requires only a limited number of follicles selected to grow at a particular time while most remain quiescent.However,the underlining mechanism is unknown.Ovarian intervention,for example ovarian cystectomy,ovarian wedge resection,or laser drilling therapies for polycystic ovarian syndrome(PCOS),has long been reported to change follicular development by an unknown mechanism(s).We established a murine model with partial ovarian resection of one ovary unilaterally,with the contralateral ovary undamaged.We found the injury accelerated follicular activation and development through the mTORC1 signaling pathway.Moreover,the stimulation of primordial follicles was restricted near the incision site where the mTORC1 pathway showed sequential activation beginning at the interstitial cells and proceeding to the primordial follicles.Total and polysome-associated RNA-seq revealed the increase of the nerve growth factor family member,NGF in both two fractions and immunostaining showed the restricted induction of NGF near the incision site.In cultured newborn ovaries.NGF demonstrated increase of follicular activation,and moreover,the NGF inhibitor K252a effectively blocked activation of primordial follicles stimulated by the surgery.We liken ovulation in mammals to minor tissue trauma,which happens naturally and cyclically in the body;and found the increase in NGF was accompanied with the accumulation of activated primordial follicles after ovulation.Herein,we propose a common mechanism for selective follicular activation induced by a localized increase in NGF in interstitial cells and mediated via the mTOR signaling pathway.Additionally,the NGF inhibitor K252a and the mTOR inhibitor rapamycin constitute good candidates for protecting follicular reserve against over exhaustion after ovarian surgery.