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.

  • Letter
  • Published:

Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates

A Corrigendum to this article was published on 01 December 2005

Abstract

The evolutionarily conserved planar cell polarity (PCP) pathway (or noncanonical Wnt pathway) drives several important cellular processes, including epithelial cell polarization, cell migration and mitotic spindle orientation1. In vertebrates, PCP genes have a vital role in polarized convergent extension movements during gastrulation and neurulation2. Here we show that mice with mutations in genes involved in Bardet-Biedl syndrome (BBS), a disorder associated with ciliary dysfunction3,4, share phenotypes with PCP mutants including open eyelids, neural tube defects and disrupted cochlear stereociliary bundles. Furthermore, we identify genetic interactions between BBS genes and a PCP gene in both mouse (Ltap, also called Vangl2) and zebrafish (vangl2). In zebrafish, the augmented phenotype results from enhanced defective convergent extension movements. We also show that Vangl2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins. These data suggest that cilia are intrinsically involved in PCP processes.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Examination of Mkks−/− mouse retinas and olfactory cilia.
Figure 2: Exencephaly in Bbs4−/− mice.
Figure 3: Cochlear stereociliary bundle examination in mutant mice.
Figure 4: Ranked mean DPOAE levels for mice and summary of hearing thresholds in human individuals with BBS.
Figure 5: Injection of tri zebrafish embryos with bbs4-MO.
Figure 6: Subcellular localization of Vangl2.

Similar content being viewed by others

References

  1. Torban, E., Kor, C. & Gros, P. Van Gogh-like2 (Strabismus) and its role in planar cell polarity and convergent extension in vertebrates. Trends Genet. 20, 570–577 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Keller, R. Shaping the vertebrate body plan by polarized embryonic cell movements. Science 298, 1950–1954 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Ansley, S.J. et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425, 628–633 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Li, J.B. et al. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117, 541–552 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Lu, X. et al. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature 430, 93–98 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Montcouquiol, M. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Curtin, J.A. et al. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr. Biol. 13, 1129–1133 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Beales, P.L. Lifting the lid on Panandora's box: the Bardet-Biedl syndrome. Curr. Opin. Genet. Dev. 15, 315–323 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Avidor-Reiss, T. et al. Decoding cilia function: Defining specialized genes required for compartmentalized cilia biogenesis. Cell 117, 527–539 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Blacque, O.E. et al. Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev. 18, 1630–1642 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim, J.C. et al. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat. Genet. 36, 462–470 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Kulaga, H.M. et al. Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse. Nat. Genet. 36, 994–998 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Mykytyn, K. et al. Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proc. Natl. Acad. Sci. USA 101, 8664–8669 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nishimura, D.Y. et al. Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proc. Natl. Acad. Sci. USA 101, 16588–16593 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fath, M.A. et al. Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome. Hum. Mol. Genet. 14, 1109–1118 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Karmous-Benailly, H. et al. Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome. Am. J. Hum. Genet. 76, 493–504 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Frolenkov, G.I., Belyantseva, I.A., Friedman, T.B. & Griffith, A.J. Genetic insights into the morphogenesis of inner ear hair cells. Nat. Rev. Genet. 5, 489–498 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Kemp, D.T. Otoacoustic emissions, travelling waves and cochlear mechanisms. Hear. Res. 22, 95–104 (1986).

    Article  CAS  PubMed  Google Scholar 

  19. Carreira-Barbosa, F. et al. Prickle 1 regulates cell movements during gastrulation and neuronal migration in zebrafish. Development 130, 4037–4046 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Jessen, J.R. et al. Zebrafish trilobite identifies new roles for Strabismus in gastrulation and neuronal movements. Nat. Cell Biol. 4, 610–615 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bingham, S., Higashijima, S., Okamoto, H. & Chandrasekhar, A. The Zebrafish trilobite gene is essential for tangential migration of branchiomotor neurons. Dev. Biol. 242, 149–160 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim, J.C. et al. MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis. J. Cell Sci. 118, 1007–1020 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Simons, M. et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signalling pathways. Nat. Genet. 37, 537–543 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zambrowicz, B.P. et al. Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells. Nature 392, 608–611 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Murdoch, J.N., Doudney, K., Paternotte, C., Copp, A.J. & Stanier, P. Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification. Hum. Mol. Genet. 10, 2593–2601 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Beales, P.L., Elcioglu, N., Woolf, A.S., Parker, D. & Flinter, F.A. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J. Med. Genet. 36, 437–446 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Morrell, C.H., Gordon-Salant, S., Pearson, J.D., Brant, L.J. & Fozard, J.L. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. J. Acoust. Soc. Am. 100, 1949–1967 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Denman-Johnson, K. & Forge, A. Establishment of hair bundle polarity and orientation in the developing vestibular system of the mouse. J. Neurocytol. 28, 821–835 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Ali, R.R. et al. Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat. Genet. 25, 306–310 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Barth, K.A. & Wilson, S.W. Expression of zebrafish nk2.2 is influenced by sonic hedgehog/vertebrate hedgehog-1 and demarcates a zone of neuronal differentiation in the embryonic forebrain. Development 121, 1755–1768 (1995).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank P. Scambler, D. Savery, N. Greene, H. Omran, N. Guo and J. Nathans for their technical help and comments in preparing this manuscript. This study was supported by grants from the Wellcome Trust (A.J.R., J.H. and A.J.C.), Medical Research Council (H.M.-S., M.T. and J.N.M.), Birth Defects Foundation (J.H.), Defeating Deafness (A.F.), the National Institute of Child Health and Development and National Institute of Diabetes, Digestive and Kidney Disorders (US National Institutes of Health; N.K.) and British Heart Foundation (D.J.H. and H.M.P.). M.R.L acknowledges funding from Heart and Stroke Foundation of BC & Yukon and Canadian Institutes of Health Research and scholarships from Michael Smith Foundation for Health Research and Canadian Institutes of Health Research. P.L.B. is a Wellcome Trust Senior Research Fellow.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Philip L Beales.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Insertional mutagenesis of Bbs6. (PDF 338 kb)

Supplementary Fig. 2

Embryonic expression pattern of Bbs6. (PDF 2198 kb)

Supplementary Fig. 3

Evaluation of olfaction in Bbs6−/− mice. (PDF 84 kb)

Supplementary Table 1

Summary of the average age of BBS patient (by sex) expressed as the equivalent age at which such a hearing threshold would be expected in the general population. (PDF 32 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ross, A., May-Simera, H., Eichers, E. et al. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet 37, 1135–1140 (2005). https://doi.org/10.1038/ng1644

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1644

This article is cited by

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