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Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation

Nature Cell Biology volume 14, pages 140–147 (2012)Cite this article

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Abstract

Multiciliate cells function prominently in the respiratory system, brain ependyma and female reproductive tract to produce vigorous fluid flow along epithelial surfaces. These specialized cells form during development when epithelial progenitors undergo an unusual form of ciliogenesis, in which they assemble and project hundreds of motile cilia. Notch inhibits multiciliate cell formation in diverse epithelia, but how progenitors overcome lateral inhibition and initiate multiciliate cell differentiation is unknown. Here we identify a coiled-coil protein, termed multicilin, which is regulated by Notch and highly expressed in developing epithelia where multiciliate cells form. Inhibiting multicilin function specifically blocks multiciliate cell formation in Xenopus skin and kidney, whereas ectopic expression induces the differentiation of multiciliate cells in ectopic locations. Multicilin localizes to the nucleus, where it directly activates the expression of genes required for multiciliate cell formation, including foxj1 and genes mediating centriole assembly. Multicilin is also necessary and sufficient to promote multiciliate cell differentiation in mouse airway epithelial cultures. These findings indicate that multicilin initiates multiciliate cell differentiation in diverse tissues, by coordinately promoting the transcriptional changes required for motile ciliogenesis and centriole assembly.

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Figure 1: MCI morphants lack MCCs.
Figure 2: MCI induces MCC differentiation.
Figure 3: MCI acts downstream of notch to promote centriole assembly and motile cilia extension through foxj1.
Figure 4: MCI induced centriole assembly.
Figure 5: MCI activates MCC gene expression.
Figure 6: Domains required for MCI function.
Figure 7: Mouse MCI governs MCC differentiation in MTEC cultures.

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Acknowledgements

The work described here was supported by NIH grants RO1 GM096021 (C.K.) and R01 GM059823 (J.D.A.) and an AP Giannini Postdoctoral Fellowship (E.K.V). The authors thank E. Campbell for technical assistance and members of the laboratory for comments on the manuscript.

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Authors and Affiliations

  1. Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA

    J. L. Stubbs & C. Kintner

  2. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA

    E. K. Vladar & J. D. Axelrod

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  1. J. L. Stubbs
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J.L.S., E.K.V. and C.K. carried out the experimental analysis. All authors participated in aspects of project planning, data analysis and manuscript preparation.

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Correspondence to C. Kintner.

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Stubbs, J., Vladar, E., Axelrod, J. et al. Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation. Nat Cell Biol 14, 140–147 (2012). https://doi.org/10.1038/ncb2406

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