The endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase G pathway activates primordial follicles.
The endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase G pathway activates primordial follicles.
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内皮一氧化氮合酶/环磷酸鸟苷/蛋白激酶G途径激活原始卵泡
DOI：
10.18632/aging.202235
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发表时间：
2020-12-03
期刊：
影响因子：
--
通讯作者：
Chen Z
中科院分区：
文献类型：
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作者：
Zhao P;Song Z;Wang Y;Cai H;Du X;Li C;Lv J;Liu X;Guo M;Chen Z
在哺乳动物中，静止原始卵泡的良好组织激活对于雌性生殖储备至关重要。在本研究中，我们研究了小鼠原始卵泡激活的机制。我们发现，内皮型一氧化氮合酶（eNOS）及其下游效应，环磷酸鸟苷（cGMP）和cGMP依赖的蛋白激酶G（PKG），表达在前颗粒细胞和促进原始卵泡激活，卵母细胞的生长和颗粒细胞增殖在新生儿卵巢。哺乳动物雷帕霉素靶蛋白（mTOR）与PKG共定位于前颗粒细胞中，并且对于eNOS/cGMP/PKG途径诱导的原始卵泡激活是必需的。发现eNOS/cGMP/PKG途径稳定mTOR蛋白。新生儿卵巢中F-box和WD重复结构域7（FBXW 7）（一种E3泛素连接酶）的mRNA水平与mTOR蛋白水平呈负相关。FBXW 7以泛素/蛋白酶体依赖性方式结合前颗粒细胞中的mTOR蛋白并使其不稳定。然而，eNOS/cGMP/PKG通路的激动剂降低FBXW 7 mRNA水平。FBXW 7过表达可抑制原始卵泡的激活，并阻止eNOS/cGMP/PKG通路激活原始卵泡和稳定mTOR蛋白。这些发现表明，eNOS/cGMP/PKG通路通过抑制FBXW 7诱导的小鼠mTOR泛素化来激活原始卵泡。
In mammals, the well-organized activation of quiescent primordial follicles is pivotal for female reproductive reserve. In the present study, we examined the mechanisms underlying primordial follicle activation in mice. We found that endothelial nitric oxide synthase (eNOS) and its downstream effectors, cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase G (PKG), were expressed in pre-granulosa cells and promoted primordial follicle activation, oocyte growth and granulosa cell proliferation in neonatal ovaries. Mammalian target of rapamycin (mTOR) colocalized with PKG in pre-granulosa cells and was essential for eNOS/cGMP/PKG pathway-induced primordial follicle activation. The eNOS/cGMP/PKG pathway was found to stabilize mTOR protein. The mRNA levels of F-box and WD repeat domain containing 7 (FBXW7), an E3 ubiquitin ligase, correlated negatively with mTOR protein levels in neonatal ovaries. FBXW7 bound to and destabilized mTOR protein in pre-granulosa cells in a ubiquitin/proteasome-dependent manner. However, agonists of the eNOS/cGMP/PKG pathway reduced FBXW7 mRNA levels. FBXW7 overexpression suppressed primordial follicle activation and prevented the eNOS/cGMP/PKG pathway from activating primordial follicles and stabilizing mTOR protein. These findings demonstrate that the eNOS/cGMP/PKG pathway activates primordial follicles by suppressing FBXW7-induced ubiquitination of mTOR in mice.