Khoury Damaa Michella, Serizay Jacques, Balagué Rémi, Boudjema Amélie-Rose, Faucourt Marion, Delgehyr Nathalie, Goh Kim Jee, Lu Hao, Tan Ee Kim, James Cameron T, Faucon Catherine, Mitri Rana, Bracht Diana Carolin, Bingle Colin D, Dunn Norris Ray, Arnold Sebastian J, Zaragosi Laure-Emmanuelle, Barbry Pascal, Koszul Romain, Omran Heymut, Gil-Gómez Gabriel, Escudier Estelle, Legendre Marie, Roy Sudipto, Spassky Nathalie, Meunier Alice
Institut de Biologie de l'ENS (IBENS), CNRS, INSERM, Ecole Normale Supérieure, PSL Research University, Paris, France.
Institut de Biologie de l'ENS (IBENS), CNRS, INSERM, Ecole Normale Supérieure, PSL Research University, Paris, France; Institut Pasteur, CNRS UMR3525, Université Paris Cité, Unité Régulation Spatiale des Génomes, Paris, France.
Cell Rep. 2025 Jan 28;44(1):115117. doi: 10.1016/j.celrep.2024.115117. Epub 2024 Dec 30.
Multiciliated cells (MCCs) ensure fluid circulation in various organs. Their differentiation is marked by the amplification of cilia-nucleating centrioles, driven by a genuine cell-cycle variant, which is characterized by wave-like expression of canonical and non-canonical cyclins such as Cyclin O (CCNO). Patients with CCNO mutations exhibit a subtype of primary ciliary dyskinesia called reduced generation of motile cilia (RGMC). Here, we show that Ccno is activated at the crossroads of the onset of MCC differentiation, the entry into the MCC cell-cycle variant, and the activation of the centriole biogenesis program. Its absence blocks the G/S-like transition of the cell-cycle variant, interrupts the centriologenesis transcription program, and compromises the production of centrioles and cilia in mouse brain and human respiratory MCCs. Altogether, our study identifies CCNO as a core regulator of entry into the MCC cell-cycle variant and the interruption of this variant as one etiology of RGMC.
多纤毛细胞（MCCs）确保各种器官中的液体循环。它们的分化以纤毛成核中心粒的扩增为标志，这是由一种真正的细胞周期变体驱动的，其特征是典型和非典型细胞周期蛋白如细胞周期蛋白O（CCNO）呈波浪状表达。CCNO突变患者表现出一种原发性纤毛运动障碍亚型，称为运动性纤毛生成减少（RGMC）。在这里，我们表明Ccno在MCC分化开始、进入MCC细胞周期变体以及中心粒生物发生程序激活的交叉点被激活。它的缺失会阻断细胞周期变体的G/S样转变，中断中心粒发生转录程序，并损害小鼠大脑和人类呼吸道MCCs中中心粒和纤毛的产生。总之，我们的研究确定CCNO是进入MCC细胞周期变体的核心调节因子，而这种变体的中断是RGMC的一种病因。
