GSE201773
Identification of a new type of endocycle during multiciliated cell differentiation
Centriole duplication and DNA replication are two tightly synchronized events of the cell cycle. Perturbations of this coordination lead to genomic instabilities and increased cancer pathologies. Yet, uncoupling of these two molecular events can occur in physiological contexts, such as in post-mitotic multiciliated cell (MCCs) differentiation, during which the activity of the mitotic oscillator is finely tuned to allow centriole amplification while preventing nuclear and cell division. Using single-cell RNA sequencing of MCC-containing tissues, we uncovered that up to 70% of the cell cycle genes are actually co-opted in differentiating MCC progenitors. These progenitors progress through differentiation following a circular transcriptional trajectory characterized by consecutives cell cycle-like phases and successive waves of cyclin expression, mimicking the canonical cell cycle. However, non-canonical cyclins replace cyclins involved in DNA synthesis and mitosis onset, potentially explaining the absence of DNA replication and cell division. Altogether, our results suggest that post-mitotic multiciliated cells have evolved across tissues and mammals by reusing the cell cycle protein toolbox but also the optimality principles of gene expression regulation of the cell cycle, to orchestrate the elaborated stepwise centriole amplification dynamics. This prompts us to propose the existence of a new type of endocycle, where multiciliating cell achieves cytoplasmic organelle amplification rather than ploidy amplification, while still escaping cell division, as in other endocycles. Overall design: scRNAseq was performed in duplicates for primary cultures of dissected brain lateral ventricular walls from newborn mice, to profile the multiciliated cell differentiation lineage.