Du Xing, Zhang Lifan, Li Xinyu, Pan Zengxiang, Liu Honglin, Li Qifa
College of Animal Science and Technology, Department of Animal Genetics, Breeding and Reproduction, Nanjing Agricultural University, Nanjing, China.
Cell Death Dis. 2016 Nov 24;7(11):e2476. doi: 10.1038/cddis.2016.379.
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.
促卵泡激素受体（FSHR）及其细胞内信号传导控制着哺乳动物卵泡的发育和女性不孕。我们之前的研究表明，在猪卵巢卵泡闭锁过程中FSHR表达下调。然而，其在卵泡闭锁中的作用和调控机制仍不清楚。在此，我们发现敲低FSHR可诱导猪颗粒细胞（pGC）凋亡和卵泡闭锁，并降低细胞内信号分子如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过程中上调的微小RNA。miR-143通过靶向FSHR增强pGC凋亡，并降低细胞内信号分子水平。SMAD4是转化生长因子（TGF）-β信号传导的终末分子，在体外和体内均与启动子结合并诱导miR-143显著下调。激活的TGF-β信号传导可挽救miR-143降低的FSHR和细胞内信号分子水平，以及miR-143诱导的pGC凋亡。总体而言，我们的研究结果为解释TGF-β信号传导如何通过特定的微小RNA miR-143影响FSHR信号传导以调控pGC凋亡和卵泡闭锁提供了证据。
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