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Calibrated mitotic oscillator drives motile ciliogenesis

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Science  10 Nov 2017:
Vol. 358, Issue 6364, pp. 803-806
DOI: 10.1126/science.aan8311

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Taming mitosis for differentiation

The mitotic oscillator consists of molecular switches known to drive cell division forward. This conserved clocklike regulatory circuit has not previously been implicated in cellular processes other than division. Multiciliated cells generate motile cilia-powered flows that are essential for brain, respiratory, and reproductive functions. Al Jord et al. found that the mitotic oscillator was activated in a calibrated fashion in terminally differentiating progenitors of multiciliated cells (see the Perspective by Levine and Holland). The oscillator function was used to drive massive production of cilia-nucleating centrioles while avoiding mitotic commitment. Thus, mammalian postmitotic progenitors can recruit and calibrate the mitotic oscillator to impose timing and directionality of cellular differentiation instead of proliferation.

Science, this issue p. 803; see also p. 716

Abstract

Cell division and differentiation depend on massive and rapid organelle remodeling. The mitotic oscillator, centered on the cyclin-dependent kinase 1–anaphase-promoting complex/cyclosome (CDK1-APC/C) axis, spatiotemporally coordinates this reorganization in dividing cells. Here we discovered that nondividing cells could also implement this mitotic clocklike regulatory circuit to orchestrate subcellular reorganization associated with differentiation. We probed centriole amplification in differentiating mouse-brain multiciliated cells. These postmitotic progenitors fine-tuned mitotic oscillator activity to drive the orderly progression of centriole production, maturation, and motile ciliation while avoiding the mitosis commitment threshold. Insufficient CDK1 activity hindered differentiation, whereas excessive activity accelerated differentiation yet drove postmitotic progenitors into mitosis. Thus, postmitotic cells can redeploy and calibrate the mitotic oscillator to uncouple cytoplasmic from nuclear dynamics for organelle remodeling associated with differentiation.

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