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A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition

Nature Genetics volume 43, pages 776–784 (2011)Cite this article

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Abstract

Mutations affecting ciliary components cause ciliopathies. As described here, we investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel and Joubert syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2 and Cc2d2a. Components of this complex co-localize at the transition zone, a region between the basal body and ciliary axoneme. Like Tctn1, loss of Tctn2, Tmem67 or Cc2d2a causes tissue-specific defects in ciliogenesis and ciliary membrane composition. Consistent with a shared function for complex components, we identified a mutation in TCTN1 that causes Joubert syndrome. Thus, a transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies.

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Figure 1: Tctn1 is required for ciliogenesis in a tissue-dependent manner.
Figure 2: Tctn1 interacts with ciliopathy proteins.
Figure 3: Tctn1 and its interactors localize to the ciliary transition zone.
Figure 4: Tctn2, like Tctn1, is essential for ciliogenesis in a tissue-dependent manner.
Figure 5: Tctn1 interactors Cc2d2a and Tmem67 promote ciliogenesis.
Figure 6: Tctn1 and its interactors control the localization of select ciliary membrane proteins.
Figure 7: A human TCTN1 mutation is a cause of Joubert syndrome.

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Acknowledgements

We thank the Institute for Regeneration Medicine and Nikon Imaging Centers at University of California San Francisco. The Servei Central de Suport a la Investigació Experimental and M. Soriano-Navarro assisted with electron microscopy. Members of the Reiter lab provided valuable discussions. K. Anderson, D. Beier, J. Gleeson, C. Johnson, H. Khanna, R. Molday, K. Mykytyn, G. Pazour, S. Scales, J. Sillibourne and S. Somlo provided antibodies or plasmids. T.R.N. is supported by a National Science Foundation predoctoral grant and an National Institute for General Medical Sciences-Initiative for Maximizing Student Diversity grant (R25-GM56847). N.K. is a Distinguished George W. Brumley Professor. F.H. is an investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist and a Frederick G. L. Huetwell Professor. This work was funded by grants from the US National Institutes of Health to N.K. (HD04260, DK072301, DK075972), F.H. (DK1069274, DK1068306, RC4-K090917) and to J.F. Reiter (AR054396), and from the March of Dimes, the Burroughs Wellcome Fund, the Packard Foundation and the Sandler Family Supporting Foundation to J.F. Reiter.

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Author notes

  1. Francesc R Garcia-Gonzalo and Kevin C Corbit: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA

    Francesc R Garcia-Gonzalo, Kevin C Corbit, Thomas R Noriega, Allen D Seol & Jeremy F Reiter

  2. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA

    Francesc R Garcia-Gonzalo, Kevin C Corbit, Allen D Seol & Jeremy F Reiter

  3. Laboratorio de Morfología Celular, Unidad Mixta Centro de Investigación Príncipe Felipe-Universidad de Valencia, Centro de Investigación Biomédica en Red (CIBERNED), Valencia, Spain

    María Salomé Sirerol-Piquer & José Manuel García-Verdugo

  4. Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA

    Gokul Ramaswami, Edgar A Otto & Friedhelm Hildebrandt

  5. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA

    Gokul Ramaswami, Edgar A Otto & Friedhelm Hildebrandt

  6. Department of Cell Biology, Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA

    Jon F Robinson, Christopher L Bennett & Nicholas Katsanis

  7. Department of Pediatrics, Duke University, Durham, North Carolina, USA

    Jon F Robinson, Christopher L Bennett & Nicholas Katsanis

  8. Department of Clinical Genetics, Guy's Hospital, London, UK

    Dragana J Josifova

  9. Department of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain

    José Manuel García-Verdugo

  10. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Friedhelm Hildebrandt

Authors
  1. Francesc R Garcia-Gonzalo
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Contributions

F.R.G.-G. and K.C.C. performed most of the experiments and wrote the manuscript. M.S.S.-P. did most of the electron microscopy and was supervised by J.M.G.-V. Human genetics were supervised by F.H. and N.K. and performed by G.R., E.A.O., D.J.J., C.L.B. and J.F. Robinson. T.R.N. performed the gel filtration chromatography. A.D.S. helped with mouse experiments. J.F. Reiter wrote the manuscript and supervised the work.

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Correspondence to Jeremy F Reiter.

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Tctn1-LAP interactors (XLS 201 kb)

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Garcia-Gonzalo, F., Corbit, K., Sirerol-Piquer, M. et al. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet 43, 776–784 (2011). https://doi.org/10.1038/ng.891

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