TGF-β signaling controls FSHR signaling-reduced ovarian granulosa cell apoptosis through the SMAD4/miR-143 axis.
TGF-β signaling controls FSHR signaling-reduced ovarian granulosa cell apoptosis through the SMAD4/miR-143 axis.
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TGF-β信号通过SMAD4/miR-143轴控制FSHR信号减少卵巢颗粒细胞凋亡
DOI：
10.1038/cddis.2016.379
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发表时间：
2016-11-24
影响因子：
9
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Du X;Zhang L;Li X;Pan Z;Liu H;Li Q
促卵泡激素受体（FSHR）及其胞内信号转导调控哺乳动物卵泡发育和女性不育。我们的前期研究表明，FSHR在猪卵泡闭锁过程中表达下调。然而，其在卵泡闭锁中的作用和调节仍不清楚。在此，我们发现FSHR敲低诱导猪颗粒细胞（pGC）凋亡和卵泡闭锁，并减弱细胞内信号分子如PKA，AKT和p-AKT的水平。FSHR被鉴定为miR-143的靶标，miR-143是一种在猪卵泡闭锁期间上调的microRNA。miR-143通过靶向FSHR促进pGC凋亡，并降低细胞内信号分子的水平。SMAD 4是转化生长因子（TGF）-β信号传导的最终分子，与启动子结合并在体外和体内诱导miR-143的显著下调。活化的TGF-β信号转导挽救了miR-143减少的FSHR和细胞内信号分子，以及miR-143诱导的pGC凋亡。总的来说，我们的研究结果提供了证据来解释TGF-β信号传导如何影响FSHR信号传导，以通过特定的microRNA miR-143调节pGC凋亡和卵泡闭锁。
Follicle-stimulating hormone receptor (FSHR) and its intracellular signaling control mammalian follicular development and female infertility. Our previous study showed that FSHR is downregulated during follicular atresia of porcine ovaries. However, its role and regulation in follicular atresia remain unclear. Here, we showed that FSHR knockdown induced porcine granulosa cell (pGC) apoptosis and follicular atresia, and attenuated the levels of intracellular signaling molecules such as PKA, AKT and p-AKT. FSHR was identified as a target of miR-143, a microRNA that was upregulated during porcine follicular atresia. miR-143 enhanced pGC apoptosis by targeting FSHR, and reduced the levels of intracellular signaling molecules. SMAD4, the final molecule in transforming growth factor (TGF)-β signaling, bound to the promoter and induced significant downregulation of miR-143 in vitro and in vivo. Activated TGF-β signaling rescued miR-143-reduced FSHR and intracellular signaling molecules, and miR-143-induced pGC apoptosis. Overall, our findings offer evidence to explain how TGF-β signaling influences and FSHR signaling for regulation of pGC apoptosis and follicular atresia by a specific microRNA, miR-143.