RhoA介导的G12-G13信号维持肌肉干细胞的静止状态并防止干细胞丢失。

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-07-16 DOI:10.1038/s41421-024-00696-7
Yundong Peng, Jingjing Du, Rui Li, Stefan Günther, Nina Wettschureck, Stefan Offermanns, Yan Wang, Andre Schneider, Thomas Braun
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引用次数: 0

摘要

多种过程控制肌肉干细胞(MuSCs)的静止,这对保证干细胞池的长期补充至关重要。在这里,我们描述了G蛋白G12-G13整合来自不同G蛋白偶联受体(GPCR)的信号,通过激活RhoA控制MuSC的静止。对GPCR配体的全面筛选发现了两种来源于MuSC-niche的因子,即内皮素-3(ET-3)和神经营养素(NT),它们能激活MuSCs中的G12-G13信号。用ET-3或NT刺激可阻止MuSC的活化,而ET-3或NT的药理抑制可减轻MuSC的静止。Gna12-Gna13或Rhoa的失活,而不是Gnaq-Gna11的失活,可完全终止MuSC的静止,这将耗尽MuSC池,并与衰老过程中的肌少症加速有关。组成型活性 RhoA 的表达能阻止 Gna12-Gna13 突变体 MuSCs 从静止中退出,通过 Rock 和甲形蛋白抑制细胞周期的进入和分化,而不影响 Rac1 依赖性 MuSC 投射,这是静止 MuSCs 的标志。这项研究揭示了G12-G13和RhoA信号在主动调节MuSC静止过程中的关键作用。
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RhoA-mediated G12-G13 signaling maintains muscle stem cell quiescence and prevents stem cell loss.

Multiple processes control quiescence of muscle stem cells (MuSCs), which is instrumental to guarantee long-term replenishment of the stem cell pool. Here, we describe that the G-proteins G12-G13 integrate signals from different G-protein-coupled receptors (GPCRs) to control MuSC quiescence via activation of RhoA. Comprehensive screening of GPCR ligands identified two MuSC-niche-derived factors, endothelin-3 (ET-3) and neurotensin (NT), which activate G12-G13 signaling in MuSCs. Stimulation with ET-3 or NT prevented MuSC activation, whereas pharmacological inhibition of ET-3 or NT attenuated MuSC quiescence. Inactivation of Gna12-Gna13 or Rhoa but not of Gnaq-Gna11 completely abrogated MuSC quiescence, which depleted the MuSC pool and was associated with accelerated sarcopenia during aging. Expression of constitutively active RhoA prevented exit from quiescence in Gna12-Gna13 mutant MuSCs, inhibiting cell cycle entry and differentiation via Rock and formins without affecting Rac1-dependent MuSC projections, a hallmark of quiescent MuSCs. The study uncovers a critical role of G12-G13 and RhoA signaling for active regulation of MuSC quiescence.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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