Gremlin 1 regulates granulosa cell apoptosis through the TGF-β/SMAD signaling pathway during bovine follicular atresia

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology Pub Date : 2025-06-25 DOI:10.1016/j.mce.2025.112605

Yupeng Xu , Mingming Liu , Ting Yang , Baoli Zhao , Yao Li , Jie Wang , Yiqun Wang , Pengfei Lin , Huatao Chen , Aihua Wang , Yaping Jin , Keqiong Tang

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引用次数: 0

Abstract

Gremlin 1 is a highly conserved secretory glycoprotein of the DAN family that plays significant roles in human and mouse follicular development and ovulation through both BMP-dependent and BMP-independent pathways. However, its function and mechanisms in bovine follicular development and atresia remain unclear. This study investigated its specific molecular mechanism during follicular development in bovines. Gremlin 1 protein is expressed in ovarian follicles at various developmental stages, with both its mRNA and protein levels increasing in correlation with the progression of follicular atresia. Following Si-RNA mediated knockdown of Gremlin 1 expression, a reduction in apoptosis and an enhancement in proliferative activity were observed in granulosa cells (GCs). In contrast, recombinant human Gremlin 1 (Rh-Gremlin 1) protein significantly induced apoptosis of GCs and inhibited cell proliferation. Previous studies have shown that Gremlin 1 can mediate apoptosis in a variety of cells through the TGF-β/SMAD signaling pathway. In our study, we observed that Gremlin 1 was associated with the phosphorylation levels of SMAD-2/3, and treatment with the TGF-β signaling pathway inhibitor SB431542 partially reversed Gremlin 1-induced apoptosis of GCs. Moreover, SB431542 significantly restored the proliferative viability and cell cycle progression of GCs. The results showed that Gremlin 1 was involved in follicular atresia-related processes by regulating the apoptosis and proliferation of GCs, and partially mediated this process through the TGF-β/SMAD signaling pathway. This provides a new avenue for further exploration of its role in follicular development.

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Gremlin 1通过TGF-β/SMAD信号通路调控牛卵泡闭锁期间颗粒细胞凋亡。

Gremlin 1是一种高度保守的DAN家族分泌糖蛋白，通过bmp依赖性和bmp非依赖性途径在人和小鼠卵泡发育和排卵中发挥重要作用。然而，其在牛卵泡发育和闭锁中的作用和机制尚不清楚。本研究探讨了其在牛卵泡发育过程中的具体分子机制。Gremlin 1蛋白在卵巢不同发育阶段的卵泡中均有表达，其mRNA和蛋白水平均随着卵泡闭锁的进展而升高。Si-RNA介导的Gremlin 1表达下调后，颗粒细胞（GCs）凋亡减少，增殖活性增强。重组人Gremlin 1 （Rh-Gremlin 1）蛋白显著诱导GCs凋亡，抑制细胞增殖。既往研究表明，Gremlin 1可通过TGF-β/SMAD信号通路介导多种细胞凋亡。在我们的研究中，我们观察到Gremlin 1与SMAD-2/3的磷酸化水平相关，TGF-β信号通路抑制剂SB431542治疗部分逆转了Gremlin 1诱导的GCs凋亡。此外，SB431542显著恢复了GCs的增殖活力和细胞周期进程。结果表明，Gremlin 1通过调控GCs的凋亡和增殖参与滤泡闭锁相关过程，并通过TGF-β/SMAD信号通路部分介导这一过程。这为进一步探索其在卵泡发育中的作用提供了新的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular and Cellular Endocrinology 医学-内分泌学与代谢

CiteScore

9.00

自引率

2.40%

发文量

174

审稿时长

42 days

期刊介绍： Molecular and Cellular Endocrinology was established in 1974 to meet the demand for integrated publication on all aspects related to the genetic and biochemical effects, synthesis and secretions of extracellular signals (hormones, neurotransmitters, etc.) and to the understanding of cellular regulatory mechanisms involved in hormonal control.