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An Alternative Cell Cycle Coordinates Multiciliated Cell Differentiation
The canonical mitotic cell cycle coordinates DNA replication, centriole duplication and cytokinesis to generate two cells from one. Some cells, such as mammalian trophoblast giant cells, employ cell cycle variants like the endocycle to bypass mitosis. Differentiating multiciliated cells, found in the mammalian airway, brain ventricles and reproductive tracts, are post-mitotic but generate hundreds of centrioles, each of which matures into a basal body and nucleates a motile cilium. Several cell cycle regulators have previously been implicated in specific steps of multiciliated cell differentiation. We found that differentiating multiciliated cells integrate cell cycle regulators into a novel cell cycle variant, 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-CDK4/6, 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 expression of genes encoding DNA replication machiner and terminates the S phase-like gene expression program. Loss of E2F7 causes a reacquisition of DNA synthesis in multiciliated cells and dysregulation of multiciliation cycle progression, disrupting centriole maturation and ciliogenesis. We conclude that multiciliated cells employ an alternative cell cycle that, instead of controlling proliferation, orchestrates differentiation.
Speakers
Semil Choksi