Disrupted glucocorticoid receptor cell signalling causes a ciliogenesis defect in the fetal mouse renal tubule.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-06-01 Epub Date: 2025-04-17 DOI:10.1038/s44319-025-00454-0

Kelly L Short, Jianshen Lao, Rachel Lam, Julie L M Moreau, Judy Ng, Mehran Piran, Alexander N Combes, Denny L Cottle, Timothy J Cole

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Abstract

Primary cilia are cell signalling and environment sensing organelles and have important roles during embryogenesis and homeostasis. We demonstrate glucocorticoid signalling is essential for normal cilia formation in mouse and human renal tubules. RNA sequencing of E18.5 kidneys from glucocorticoid receptor (GR) null mice identified significant reductions in key ciliogenesis-related genes including Ccp110, Cep97, Cep290 and Kif3a. Confocal microscopy reveals abnormal, stunted cilia on proximal tubules, podocytes, and collecting duct cells in mice with global or conditional deletion of GR. In contrast, activation of GR signalling with dexamethasone in human kidney organoids or mouse IMCD3 cells increases cilia length, an effect blocked by the GR antagonist RU486. Analysis of GR-null kidney extracts demonstrates reduced levels of pERK and SUFU identifying potential cell pathway crosstalk with GR signalling that coordinately regulate ciliogenesis in the renal tubule. Finally, dexamethasone reduces Aurora kinase A levels, a factor driving cilia disassembly and implicated in the pathogenesis of polycystic kidney disease.

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糖皮质激素受体细胞信号传导中断导致胎鼠肾小管纤毛发生缺陷。

初级纤毛是细胞信号传递和环境感知的细胞器，在胚胎发生和体内平衡中起着重要作用。我们证明糖皮质激素信号是必不可少的正常纤毛形成在小鼠和人肾小管。糖皮质激素受体（GR）缺失小鼠E18.5肾脏的RNA测序发现，包括Ccp110、Cep97、Cep290和Kif3a在内的关键纤毛相关基因显著减少。共聚焦显微镜显示，在GR整体缺失或条件缺失的小鼠中，近端小管、足细胞和收集管细胞上的纤毛异常、发育不良。相反，在人肾类器官或小鼠IMCD3细胞中，地塞米松激活GR信号会增加纤毛长度，这一作用被GR拮抗剂RU486阻断。对GR-null肾提取物的分析表明，pERK和SUFU水平降低，表明GR信号与肾小管中协调调节纤毛发生的潜在细胞通路串扰。最后，地塞米松降低极光激酶A水平，这是一种驱动纤毛解体的因素，与多囊肾病的发病机制有关。

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

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.