An alternative cell cycle coordinates multiciliated cell differentiation.

Autor: Choksi SP; Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. semil.choksi@ucsf.edu., Byrnes LE; Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA., Konjikusic MJ; Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA., Tsai BWH; Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA., Deleon R; Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA., Lu Q; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Westlake CJ; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Reiter JF; Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. jeremy.reiter@ucsf.edu.; Chan Zuckerberg Biohub, San Francisco, CA, USA. jeremy.reiter@ucsf.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Jun; Vol. 630 (8015), pp. 214-221. Date of Electronic Publication: 2024 May 29.
DOI: 10.1038/s41586-024-07476-z
Abstrakt: The canonical mitotic cell cycle coordinates DNA replication, centriole duplication and cytokinesis to generate two cells from one 1 . Some cells, such as mammalian trophoblast giant cells, use cell cycle variants like the endocycle to bypass mitosis 2 . Differentiating multiciliated cells, found in the mammalian airway, brain ventricles and reproductive tract, are post-mitotic but generate hundreds of centrioles, each of which matures into a basal body and nucleates a motile cilium 3,4 . Several cell cycle regulators have previously been implicated in specific steps of multiciliated cell differentiation 5,6 . Here we show that differentiating multiciliated cells integrate cell cycle regulators into a new alternative cell cycle, which we refer to as the multiciliation cycle. The multiciliation cycle redeploys many canonical cell cycle regulators, including cyclin-dependent kinases (CDKs) and their cognate cyclins. For example, cyclin D1, CDK4 and CDK6, which are regulators of mitotic G1-to-S progression, are required to initiate multiciliated cell differentiation. The multiciliation cycle amplifies some aspects of the canonical cell cycle, such as centriole synthesis, and blocks others, such as DNA replication. E2F7, a transcriptional regulator of canonical S-to-G2 progression, is expressed at high levels during the multiciliation cycle. In the multiciliation cycle, E2F7 directly dampens the expression of genes encoding DNA replication machinery and terminates the S phase-like gene expression program. Loss of E2F7 causes aberrant acquisition of DNA synthesis in multiciliated cells and dysregulation of multiciliation cycle progression, which disrupts centriole maturation and ciliogenesis. We conclude that multiciliated cells use an alternative cell cycle that orchestrates differentiation instead of controlling proliferation.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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