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A positive feedback mechanism governs the polarity and motion of motile cilia

Nature volume 447, pages 97–101 (2007)Cite this article

Abstract

Ciliated epithelia produce fluid flow in many organ systems, ranging from the respiratory tract where it clears mucus1 to the ventricles of the brain where it transports cerebrospinal fluid2. Human diseases that disable ciliary flow, such as primary ciliary dyskinesia, can compromise organ function or the ability to resist pathogens, resulting in recurring respiratory infections, otitis, hydrocephaly and infertility3. To create a ciliary flow, the cilia within each cell need to be polarized coordinately along the planar axis of the epithelium, but how polarity is established in any ciliated epithelia is not known. Here we analyse the developmental mechanisms that polarize cilia, using the ciliated cells in the developing Xenopus larval skin as a model system4. We show that cilia acquire polarity through a sequence of events, beginning with a polar bias set by tissue patterning, followed by a refinement phase. Our results indicate that during refinement, fluid flow is both necessary and sufficient in determining cilia polarity. These findings reveal a novel mechanism in which tissue patterning coupled with fluid flow act in a positive feedback loop to direct the planar polarity of cilia.

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Figure 1: Analysis of cilia polarity using TEM.
Figure 2: Mesoderm is critical for polarized fluid flow and cilia direction.
Figure 3: Morpholinos disrupt cilia structure but not ciliated cell differentiation.
Figure 4: Cilia polarity is unrefined in tadpoles with immotile cilia.
Figure 5: Cilia polarity can be reoriented by an external fluid flow, but only when cilia are motile.

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Acknowledgements

We thank members of the laboratory for critical comments on the manuscript. We are grateful to C. Stevens and M. Dickinson for discussions. This work was supported by a NIH grant to C.K.

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Authors and Affiliations

  1. The Salk Institute for Biological Studies, La Jolla, California 92186, USA,

    Brian Mitchell, Richard Jacobs & Chris Kintner

  2. Howard Hughes Medical Institute, USA,

    Richard Jacobs

  3. Department of Bioengineering and Whitaker Institute of Biomedical Engineering, University of California San Diego, La Jolla, California 92093, USA,

    Julie Li & Shu Chien

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  1. Brian Mitchell
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Corresponding author

Correspondence to Chris Kintner.

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Supplementary information

Supplementary Information

This file contains Supplementary Figure S1 and Supplementary Table S1 with Legends and Supplementary Videos S1-S6 Legends. (PDF 1731 kb)

Supplementary Video S1

This file contains Supplementary Video S1 which shows fluid flow produced by a stage 16 explant. (MOV 417 kb)

Supplementary Video S2

This file contains Supplementary Video S2 which shows fluid flow produced by a St10 explant (MOV 266 kb)

Supplementary Video S3

This file contains Supplementary Video S3 which shows fluid flow produced by a st29 embryo injected with a control morpholino (MOV 319 kb)

Supplementary Video S4

This file contains Supplementary Video S4 which shows loss of fluid flow in TEKT2AMO/BMO injected embryos. (MOV 351 kb)

Supplementary Video S5

This file contains Supplementary Video S5 which shows visualization of cilia beating in individual ciliated cells and the loss of cilia motility in morphants. (MOV 2087 kb)

Supplementary Video S6

This file contains Supplementary Video S6 which shows St10 explant tested at St29 after treatment with 0.5 Dyn/cm2 of shear stress. (MOV 338 kb)

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Mitchell, B., Jacobs, R., Li, J. et al. A positive feedback mechanism governs the polarity and motion of motile cilia. Nature 447, 97–101 (2007). https://doi.org/10.1038/nature05771

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