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Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response

Nature Genetics volume 39, pages 13501360 (2007) | Download Citation

Abstract

Primary cilia and basal bodies are evolutionarily conserved organelles that mediate communication between the intracellular and extracellular environments. Here we show that bbs1, bbs4 and mkks (also known as bbs6), which encode basal body proteins, are required for convergence and extension in zebrafish and interact with wnt11 and wnt5b. Suppression of bbs1, bbs4 and mkks transcripts results in stabilization of β-catenin with concomitant upregulation of T-cell factor (TCF)-dependent transcription in both zebrafish embryos and mammalian ciliated cells, a defect phenocopied by the silencing of the axonemal kinesin subunit KIF3A but not by chemical disruption of the cytoplasmic microtubule network. These observations are attributable partly to defective degradation by the proteasome; suppression of BBS4 leads to perturbed proteasomal targeting and concomitant accumulation of cytoplasmic β-catenin. Cumulatively, our data indicate that the basal body is an important regulator of Wnt signal interpretation through selective proteolysis and suggest that defects in this system may contribute to phenotypes pathognomonic of human ciliopathies.

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Acknowledgements

We apologize to our colleagues whose work we were unable to cite because of a strict 50-reference limit. We thank J. Nathans, J. Axelrod, L. Menezes, G. Germino and E. Davis for their critical evaluation of this manuscript, and A. Gherman for the quantification of the western blots. We also thank J. Nathans for the gift of the 293T luciferase reporter cell line, J. Kitajewski for the mouse Wnt cDNAs, G. Walz for the gift of the Myr/Pal Dvl construct, B. Yoder for the gift of anti-polaris/IFT88 antibody and S. Leach for the validated β-catenin antibody. This work was supported by grants from the German Academic Exchange Service (J.G.), the Polycystic Kidney Disease Foundation (J.B.), the National Institute of Child Health and Development (N.K.), the National Institute of Diabetes, Digestive and Kidney disorders (N.K.), the National Institute for Arthritis and Musculoskeletal disorders (S.F.) and the Medical Research Council (P.L.B.). P.L.B. is a Senior Wellcome Trust Fellow. P.A.B. is an Investigator of the Howard Hughes Medical Institute.

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Affiliations

  1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    • Jantje M Gerdes
    • , Yangfan Liu
    • , Norann A Zaghloul
    • , Carmen C Leitch
    • , Shaneka S Lawson
    • , Shannon Fisher
    • , Jose L Badano
    •  & Nicholas Katsanis
  2. Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Masaki Kato
    •  & Philip A Beachy
  3. Molecular Medicine Unit, Institute of Child Health, University College London, WC1N 1EH, UK.

    • Philip L Beales
  4. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

    • George N DeMartino
  5. Institut Pasteur, CP11400 Montevideo, Uruguay.

    • Jose L Badano
  6. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    • Masaki Kato
    • , Philip A Beachy
    •  & Nicholas Katsanis
  7. Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    • Nicholas Katsanis

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Correspondence to Nicholas Katsanis.

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DOI

https://doi.org/10.1038/ng.2007.12

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