The epithelial Na⁺ channel (ENaC) in ovarian granulosa cells modulates Ca²⁺ mobilization and gonadotrophin signaling for estrogen homeostasis and female fertility.

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2024-08-14 DOI:10.1186/s12964-024-01778-5

Xiyang Ma, Ruiyao Xu, Junjiang Chen, Shan Wang, Peijie Hu, Yong Wu, Yanting Que, Wanting Du, Xiaojun Cai, Hui Chen, Jinghui Guo, Tin Chiu Li, Ye Chun Ruan

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Abstract

Ovarian granulosa cells are essential to gonadotrophin-regulated estrogen production, female cycle maintenance and fertility. The epithelial Na⁺ channel (ENaC) is associated with female fertility; however, whether and how it plays a role in ovarian cell function(s) remained unexplored. Here, we report patch-clamp and Na⁺ imaging detection of ENaC expression and channel activity in both human and mouse ovarian granulosa cells, which are promoted by pituitary gonadotrophins, follicle stimulating hormone (FSH) or luteinizing hormone (LH). Cre-recombinase- and CRISPR-Cas9-based granulosa-specific knockout of ENaC α subunit (Scnn1a) in mice resulted in failed estrogen elevation at early estrus, reduced number of corpus luteum, abnormally extended estrus phase, reduced litter size and subfertility in adult female mice. Further analysis using technologies including RNA sequencing and Ca²⁺ imaging revealed that pharmacological inhibition, shRNA-based knockdown or the knockout of ENaC diminished spontaneous or stimulated Ca²⁺ oscillations, lowered the capacity of intracellular Ca²⁺ stores and impaired FSH/LH-stimulated transcriptome changes for estrogen production in mouse and/or human granulosa cells. Together, these results have revealed a previously undefined role of ENaC in modulating gonadotrophin signaling in granulosa cells for estrogen homeostasis and thus female fertility.

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卵巢颗粒细胞中的上皮Na+通道（ENaC）调节Ca2+动员和促性腺激素信号传导，从而促进雌激素平衡和女性生育。

卵巢颗粒细胞对促性腺激素调节的雌激素分泌、女性生理周期维持和生育能力至关重要。上皮Na+通道（ENaC）与女性的生育能力有关；然而，它是否以及如何在卵巢细胞功能中发挥作用仍未得到探索。在此，我们报告了在垂体促性腺激素、卵泡刺激素（FSH）或黄体生成素（LH）的作用下，对人类和小鼠卵巢颗粒细胞中ENaC表达和通道活性的膜片钳和Na+成像检测。基于克隆重组酶（Cre-recombinase）和CRISPR-Cas9技术的小鼠颗粒细胞特异性ENaC α亚基（Scnn1a）敲除导致成年雌性小鼠发情早期雌激素升高失败、黄体数量减少、发情期异常延长、产仔数减少和不育。利用 RNA 测序和 Ca2+ 成像等技术进行的进一步分析表明，药物抑制、基于 shRNA 的基因敲除或 ENaC 基因敲除会削弱自发或受刺激的 Ca2+ 振荡，降低细胞内 Ca2+ 储存的能力，并损害 FSH/LH 刺激的转录组变化，从而影响小鼠和/或人类颗粒细胞中雌激素的产生。这些结果共同揭示了ENaC在调节颗粒细胞中的促性腺激素信号以促进雌激素平衡从而提高女性生育能力方面所起的作用，而这一作用之前尚未得到明确定义。

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

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.

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