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