Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Afzelius, B. A. Cilia-related diseases. J. Pathol. 204, 470–477 (2004)

    Article  CAS  Google Scholar 

  2. Sawamoto, K. et al. New neurons follow the flow of cerebrospinal fluid in the adult brain. Science 311, 629–632 (2006)

    Article  ADS  CAS  Google Scholar 

  3. Zariwala, M. A., Knowles, M. R. & Omran, H. Genetic defects in ciliary structure and function. Annu. Rev. Physiol. 69, 423–450 (2006)

    Article  Google Scholar 

  4. Assheton, R. Notes on the ciliation of the ectoderm of amphibian embryos. Q. J. Microscope Sci. 38, 465–484 (1896)

    Google Scholar 

  5. Twitty, V. C. Experimental studies on the ciliary action of amphibian embryos. J. Exp. Zool. 50, 310–344 (1928)

    Article  Google Scholar 

  6. Woerdeman, M. W, Entwicklungsmechnanische Untersuchungen uber die Wimperbewegung des Ectoderms von Amphibienlarven. Rouxs Arch. Dev. Biol. 106, 41–61 (1925)

    Article  CAS  Google Scholar 

  7. Tung, T. C. & Tung, Y.-F. Y. Experimental studies on the determination of polarity of ciliary action in anuran embryos. Arch. Biol. (Liege) 51, 203–218 (1940)

    Google Scholar 

  8. Frisch, D. & Farbman, A. I. Development of order during ciliogenesis. Anat. Rec. 162, 221–232 (1968)

    Article  CAS  Google Scholar 

  9. Konig, G. & Hausen, P. Planar polarity in the ciliated epidermis of Xenopus embryos. Dev. Biol. 160, 355–368 (1993)

    Article  CAS  Google Scholar 

  10. Roomans, G. M., Ivanovs, A., Shebani, E. B. & Johannesson, M. Transmission electron microscopy in the diagnosis of primary ciliary dyskinesia. Ups. J. Med. Sci. 111, 155–168 (2006)

    Article  Google Scholar 

  11. Nasevicius, A. & Ekker, S. C. Effective targeted gene 'knockdown' in zebrafish. Nature Genet. 26, 216–220 (2000)

    Article  CAS  Google Scholar 

  12. Sapiro, R. et al. Male infertility, impaired sperm motility, and hydrocephalus in mice deficient in sperm-associated antigen 6. Mol. Cell. Biol. 22, 6298–6305 (2002)

    Article  CAS  Google Scholar 

  13. Tanaka, H. et al. Mice deficient in the axonemal protein Tektin-t exhibit male infertility and immotile-cilium syndrome due to impaired inner arm dynein function. Mol. Cell. Biol. 24, 7958–7964 (2004)

    Article  CAS  Google Scholar 

  14. Frangos, J. A., Eskin, S. G., McIntire, L. V. & Ives, C. L. Flow effects on prostacyclin production by cultured human endothelial cells. Science 227, 1477–1479 (1985)

    Article  ADS  CAS  Google Scholar 

  15. Hsu, P. P. et al. Effects of flow patterns on endothelial cell migration into a zone of mechanical denudation. Biochem. Biophys. Res. Commun. 285, 751–759 (2001)

    Article  CAS  Google Scholar 

  16. Witzgall, R. New developments in the field of cystic kidney diseases. Curr. Mol. Med. 5, 455–465 (2005)

    Article  CAS  Google Scholar 

  17. Bush, A. et al. Primary ciliary dyskinesia: diagnosis and standards of care. Eur. Respir. J. 12, 982–988 (1998)

    Article  CAS  Google Scholar 

  18. Sive, H., Grainger, R. M. & Harland, R. M. The Early Development of Xenopus laevis: a Laboratory Manual (Cold Spring Harbor Press, Plainview, New York, 1998).

    Google Scholar 

  19. Davidson, L. A., Hoffstrom, B. G., Keller, R. & DeSimone, D. W. Mesendoderm extension and mantle closure in Xenopus laevis gastrulation: combined roles for integrin alpha(5)beta(1), fibronectin, and tissue geometry. Dev. Biol. 242, 109–129 (2002)

    Article  CAS  Google Scholar 

  20. Nieuwkoop, P. D. & Faber, J. Normal Table of Xenopus laevis (North Holland, Amersterdam, 1967)

    Google Scholar 

  21. Chien, S. in The Red Blood Cell (ed. Surgenor, M. D.) 1031–1133 (Academic Press, New York, 1975)

    Book  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Brian Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard Jacobs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shu Chien
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chris Kintner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chris Kintner.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05771

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing