Yuan Cheng, Neuner Annett, Streubel Johanna, Bhanushali Ayushi, Simons Matias, Acebrón Sergio P, Pereira Gislene
Centre for Organismal Studies (COS), Cytoskeleton, Cell Division and Signal transduction Unit, University of Heidelberg, Heidelberg, Germany.
German Cancer Research Centre (DKFZ), Molecular Biology of Centrosome and Cilia Unit, DKFZ-ZMBH Alliance, Heidelberg, Germany.
PLoS Biol. 2025 Sep 2;23(9):e3003369. doi: 10.1371/journal.pbio.3003369. eCollection 2025 Sep.
The primary cilium is a microtubule-based organelle essential for various cellular functions, particularly signal transduction. While the role of cilia in regulating signaling pathways has been extensively studied, the impact of signaling pathways on cilia formation remains less well understood. Wnt signals are critical modulators of cell fate. In this study, we investigate how modulating Wnt signaling affects cilia formation in human retinal pigment epithelial (hTERT-RPE1) cells. Our findings show that enhancement of Wnt/LRP6 signaling before serum starvation delays ciliogenesis. Cells with high baseline Wnt activity exhibited distal appendage dysregulation, failure to remove CP110-CEP97 from mother centrioles, and reduced Rab8-vesicle docking, which are critical events for cilia membrane establishment and axoneme extension. Additionally, these cells displayed reduced autophagic flux, increased mTOR kinase activity, and elevated OFD1 levels at centriolar satellites. Importantly, mTOR inhibition rescued ciliogenesis in cells with elevated Wnt activity, underscoring the interplay between these signaling pathways. Our data also indicate that insufficient Wnt signaling activation disrupts ciliogenesis, emphasizing the need for precisely regulated Wnt levels.
初级纤毛是一种基于微管的细胞器，对各种细胞功能至关重要，尤其是信号转导。虽然纤毛在调节信号通路中的作用已得到广泛研究，但信号通路对纤毛形成的影响仍了解较少。Wnt信号是细胞命运的关键调节因子。在本研究中，我们探究了调节Wnt信号如何影响人视网膜色素上皮（hTERT-RPE1）细胞中的纤毛形成。我们的研究结果表明，血清饥饿前Wnt/LRP6信号的增强会延迟纤毛发生。具有高基线Wnt活性的细胞表现出远端附属物失调、无法从母中心粒去除CP110-CEP97以及Rab8囊泡对接减少，这些都是纤毛膜建立和轴丝延伸的关键事件。此外，这些细胞的自噬通量降低、mTOR激酶活性增加以及中心粒卫星处的OFD1水平升高。重要的是，mTOR抑制挽救了Wnt活性升高的细胞中的纤毛发生，强调了这些信号通路之间的相互作用。我们的数据还表明，Wnt信号激活不足会破坏纤毛发生，强调了精确调节Wnt水平的必要性。
