Restricting the induction of NGF in ovarian stroma engenders selective follicular activation through the mTOR signaling pathway.
Restricting the induction of NGF in ovarian stroma engenders selective follicular activation through the mTOR signaling pathway.
复制标题
限制卵巢基质中 NGF 的诱导，通过 mTOR 信号通路选择性激活卵泡
DOI：
10.1038/cddis.2017.168
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发表时间：
2017-05-25
影响因子：
9
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
He Y;Peng X;Wu T;Yang W;Liu W;Zhang J;Su Y;Kong F;Dou X;Li J
在哺乳动物卵巢中，原始卵泡保持静止状态，直到被周围微环境激活。卵巢干预，例如，卵巢囊肿切除术，卵巢楔形切除术或激光钻孔治疗多囊卵巢综合征，长期以来一直被报道通过未知的机制改变卵泡发育。在此，我们建立了一个单侧卵巢部分切除的小鼠模型，对侧卵巢未受损伤。我们发现损伤通过mTORC 1信号通路加速卵泡激活和发育。此外，原始卵泡的刺激被限制在切口部位附近，其中mTORC 1通路显示从间质细胞开始并进行到原始卵泡的连续激活。总的和多核糖体相关的RNA-seq揭示了神经生长因子（NGF）家族成员在两种组分中的增加，并且免疫染色显示了切口部位附近的NGF的受限诱导。在培养的新生儿卵巢中，NGF表现出卵泡激活的增加，而且，NGF抑制剂K252 a有效地阻断了手术刺激的原始卵泡的激活。我们把哺乳动物的排卵比作轻微的组织创伤，它在体内自然周期性地发生。由于NGF的增加伴随着排卵后激活的原始卵泡的积累，我们的研究可能代表了由间质细胞中NGF的局部增加诱导并通过mTOR信号通路介导的选择性卵泡激活的共同机制。此外，NGF抑制剂K252 a和mTOR抑制剂雷帕霉素构成了保护卵泡储备免受卵巢手术后过度耗竭的良好候选物。
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.
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