SMAD4通过miR-183-96-182簇和FoxO1轴抑制颗粒细胞凋亡。

SMAD4 Inhibits Granulosa Cell Apoptosis via the miR-183-96-182 Cluster and FoxO1 Axis.

作者信息

Yao Wang, Wang Siqi, Du Xing, Lin Chenggang, Zhang Jinbi, Pan Zengxiang, Li Qifa

机构信息

College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.

出版信息

Reprod Sci. 2022 May;29(5):1577-1585. doi: 10.1007/s43032-021-00690-4. Epub 2021 Jul 21.

DOI:10.1007/s43032-021-00690-4

PMID:34287793

Abstract

The miR-183-96-182 cluster is a polycistronic miRNA cluster necessary for ovarian functions in mammals. However, its transcriptional regulation in the ovary is largely unclear. In this study, we characterized the promoter region of the porcine miR-183-96-182 cluster, and showed that SMAD4 may function as a transcriptional activator of the miR-183-96-182 cluster in GCs through direct binding to SBE motifs in its promoter. SMAD4 may inhibit GC apoptosis via suppression of FoxO1, an effector of GC apoptosis and a direct target of the miR-183-96-182 cluster, by inducing the miR-183-96-182 cluster, and this process may be regulated by the TGF-β/SMAD signaling pathway. Our findings uncovered the regulatory mechanism of miR-183-96-182 cluster expression in GCs and demonstrated that TGF-β1/SMAD4/miR-183-96-182 cluster/FoxO1 may be a potential pathway for regulating follicular atresia and female reproduction.

摘要

miR-183-96-182簇是哺乳动物卵巢功能所必需的多顺反子miRNA簇。然而，其在卵巢中的转录调控在很大程度上尚不清楚。在本研究中，我们对猪miR-183-96-182簇的启动子区域进行了表征，并表明SMAD4可能通过直接结合其启动子中的SBE基序而作为颗粒细胞中miR-183-96-182簇的转录激活因子。SMAD4可能通过诱导miR-183-96-182簇来抑制颗粒细胞凋亡，颗粒细胞凋亡的效应因子和miR-183-96-182簇的直接靶点FoxO1，并且这一过程可能受TGF-β/SMAD信号通路调控。我们的研究结果揭示了颗粒细胞中miR-183-96-182簇表达的调控机制，并证明TGF-β1/SMAD4/miR-183-96-182簇/FoxO1可能是调节卵泡闭锁和雌性生殖的潜在途径。