Restricting the induction of NGF in ovarian stroma engenders selective follicular activation through the mTOR signaling pathway

Yuanlin He,Jing Li,Xiaowei Dou,Jing Zhang,Weijie Yang,Tinghe Wu,Yiping Su,Wenwen Liu,Xiaoxu Peng,Feifei Kong

doi:10.1038/cddis.2017.168

Abstract

In mammalian ovaries, primordial follicles remain in a quiescent state until activation by the surrounding microenvironment. Ovarian intervention, for example, ovarian cystectomy, ovarian wedge resection or laser drilling therapies for polycystic ovarian syndrome, has long been reported to change follicular development by an unknown mechanism(s). Herein, 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 (NGF) family member, 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. As the increase in NGF accompanied the accumulation of activated primordial follicles after ovulation, our study may represent a common mechanism for selective follicular activation induced by a localized increase in NGF in interstitial cells and mediated via the mTOR signaling pathway. In addition, the NGF inhibitor K252a and the mTOR inhibitor rapamycin constitute good candidates for protecting follicular reserve against over exhaustion after ovarian surgery.

Highlights

In mammals, it is widely accepted that primordial follicles are assembled in finite numbers in the ovary before or around birth and remain quiescent, sometimes for decades.[1]
A recent study by Liu et al provides a picture of how mammalian primordial follicles are activated; that is, the microenvironment surrounding primordial follicles can activate mTORC1-KITL signaling in pregranulosa cells, and these cells trigger the activation of dormant oocytes through KIT-PI3K signaling.[8]
As the translational levels increased markedly in the injured ovary, it was found that the neurotrophic growth factor family member, nerve growth factor (NGF), participated in activating dormant follicles through the mTOR signaling pathway

Summary

Introduction

It is widely accepted that primordial follicles are assembled in finite numbers in the ovary before or around birth and remain quiescent, sometimes for decades.[1]. A recent study found that fragmentation of murine ovaries promoted the development of primary follicles to the late secondary stage by disrupting the Hippo signaling pathway.[12] the effects of such ovarian injury on primordial follicles and the underlying mechanism(s) involved remain unelucidated. We ask whether this represents a common mechanism in selective initial recruitment of primordial follicles. We found that a localized increase of nerve growth factor (NGF) in the ovarian stroma functioned upstream of mTOR signaling so as to activate primordial follicles after surgery

Methods

Results

Conclusion