Cyclin O controls entry into the cell-cycle variant required for multiciliated cell differentiation

Author:

Damaa Michella Khoury,Serizay JacquesORCID,Balagué Rémi,Boudjema Amélie-Rose,Faucourt Marion,Delgehyr NathalieORCID,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-Gόmez Gabriel,Escudier Estelle,Legendre Marie,Roy Sudipto,Spassky Nathalie,Meunier Alice

Abstract

AbstractMulticiliated cells (MCC) ensure proper fluid circulation in various organs in metazoans. Their differentiation is marked by the massive ampliication of cilia-nucleating centrioles and is known to be controlled by various cell cycle components. Tn a companion study, we show that the differentiation of MCC is driven by a genuine cell-cycle variant characterized by sequential and wave-like expression of canonical and non-canonical cyclins such as Cyclin O (CCNO). Patients withCCNOmutations exhibit a subtype of Primary Ciliary Dyskinesia (PCD) designated as Reduced Generation of Multiple Motile Cilia (RGMC), yet the role of CCNO during MCC differentiation remains unclear. Here, using mice and human cellular models, single cell transcriptomics and functional studies, we show thatCenais activated during a strategic temporal window at the crossroads between the onset of MCC differentiation, the entry into the MCC cell cycle variant, and the activation of the centriole biogenesis program. We ind that the absence ofCenaleads to a block of MCC progenitor differentiation at the G1/S-like transition, just before the beginning of centriole formation. This leads to a complete lack of centrioles and cilia in mouse brain and human airway MCC. Altogether, our study identifies CCNO as a core regulator of entry into the MCC cell cycle variant and shows that the coupling of centriole biogenesis to an S-like phase, maintained in MCC, is dependent on CCNO.One sentence summaryCyclin O is necessary for multiciliated cells to enter their differentiation cell cycle variant and allows the massive amplification of centrioles, which serve as basal bodies for cilia nucleation.

Publisher

Cold Spring Harbor Laboratory

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