Original Article

Citation: Cell Death and Disease (2017) 8, e2817; doi:10.1038/cddis.2017.168
Published online 25 May 2017

Restricting the induction of NGF in ovarian stroma engenders selective follicular activation through the mTOR signaling pathway
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Yuanlin He1,4, Xiaoxu Peng1,4, Tinghe Wu2, Weijie Yang1, Wenwen Liu1, Jing Zhang1, Yiping Su3, Feifei Kong1, Xiaowei Dou1 and Jing Li1

  1. 1State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
  2. 2Department of Biotechnology and Biomedicine, Yangtze Delta Region Institutes of Tsinghua University, Jiaxing, China
  3. 3Department of Gynecology, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, China

Correspondence: J Li, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Room B101, Xuehai Building, 818 Tianyuandonglu, Nanjing, Jiangsu 210029, China. Tel: +86 25 86869503; Fax: +86 25 86865903; E-mail: ljwth@njmu.edu.cn

4These authors contributed equally to this work.

Received 1 February 2017; Revised 9 March 2017; Accepted 14 March 2017

Edited by Y Shi

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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.