Letter | Published:

Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton

Nature Cell Biology volume 15, pages 11071115 (2013) | Download Citation


In ciliated mammalian cells, the precise migration of the primary cilium at the apical surface of the cells, also referred to as translational polarity, defines planar cell polarity (PCP) in very early stages. Recent research has revealed a co-dependence between planar polarization of some cell types and cilium positioning at the surface of cells. This important role of the primary cilium in mammalian cells is in contrast with its absence from Drosophila melanogaster PCP establishment. Here, we show that deletion of GTP-binding protein alpha-i subunit 3 (Gαi3) and mammalian Partner of inscuteable (mPins) disrupts the migration of the kinocilium at the surface of cochlear hair cells and affects hair bundle orientation and shape. Inhibition of G-protein function in vitro leads to kinocilium migration defects, PCP phenotype and abnormal hair bundle morphology. We show that Gαi3/mPins are expressed in an apical and distal asymmetrical domain, which is opposite and complementary to an aPKC/Par-3/Par-6b expression domain, and non-overlapping with the core PCP protein Vangl2. Thus G-protein-dependent signalling controls the migration of the cilium cell autonomously, whereas core PCP signalling controls long-range tissue PCP.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & Planar cell polarity signaling: from fly development to human disease. Annu. Rev. Genet. 42, 517–540 (2008).

  2. 2.

    , & Planar cell polarity signaling: the developing cell’s compass. Cold Spring Harb. Perspect Biol. 1, a002964 (2009).

  3. 3.

    et al. Ciliary proteins link basal body polarization to planar cell polarity regulation. Nat. Genet. 40, 69–77 (2008).

  4. 4.

    , , , & Cilia organize ependymal planar polarity. J. Neurosci. 30, 2600–2610 (2010).

  5. 5.

    et al. Planar cell polarity breaks bilateral symmetry by controlling ciliary positioning. Nature 466, 378–382 (2010).

  6. 6.

    Planar cell polarity signaling, cilia and polarized ciliary beating. Curr. Opin. Cell Biol. 22, 597–604 (2010).

  7. 7.

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

  8. 8.

    & Mitotic spindle orientation in asymmetric and symmetric cell divisions during animal development. Dev. Cell 21, 102–119 (2011).

  9. 9.

    & Revisiting planar cell polarity in the inner ear. Semin. Cell Dev. Biol. 5, 499–506 (2013).

  10. 10.

    & The PAR proteins: fundamental players in animal cell polarization. Dev. Cell 13, 609–622 (2007).

  11. 11.

    Mechanisms of asymmetric cell division: flies and worms pave the way. Nat. Rev. Mol. Cell Biol. 9, 355–366 (2008).

  12. 12.

    et al. An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver. Proc. Natl Acad. Sci. USA 104, 3003–3008 (2007).

  13. 13.

    et al. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat. Genet. 37, 1135–1140 (2005).

  14. 14.

    & Kif3a regulates planar polarization of auditory hair cellsthrough both ciliary and non-ciliary mechanisms. Development 138, 3441–3449 (2011).

  15. 15.

    , , , & Centrosomal deployment of gamma-tubulin and pericentrin: evidence for a microtubule-nucleating domain and a minus-end docking domain in certain mouse epithelial cells. Cell. Motil. Cytoskeleton 36, 276–290 (1997).

  16. 16.

    & Mammalian Pins is a conformational switch that links NuMA to heterotrimeric G proteins. Cell 119, 503–516 (2004).

  17. 17.

    Remodeling epithelial cell organization: transitions between front-rear and apical-basal polarity. Cold Spring Harb. Perspect Biol. 1, a000513 (2009).

  18. 18.

    & Maintained expression of the planar cell polarity molecule Vangl2 and reformation of hair cell orientation in the regenerating inner ear. J. Assoc. Res. Otolaryngol. 11, 395–406 (2010).

  19. 19.

    et al. Gipc1 has a dual role in Vangl2 trafficking and hair bundle integrity in the inner ear. Development 139, 3775–3785 (2012).

  20. 20.

    & Targeted knockdown of G protein subunits selectively prevents receptor-mediated modulation of effectors and reveals complex changes in non-targeted signaling proteins. J. Biol. Chem. 281, 10250–10262 (2006).

  21. 21.

    & Mouse models for dissecting vertebrate planar cell polarity signaling in the inner ear. Brain Res. 1277, 130–140 (2009).

  22. 22.

    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).

  23. 23.

    , & Tubulin expression in the developing and adult gerbil organ of Corti. Hear Res. 139, 31–41 (2000).

  24. 24.

    et al. Patterns of expression of Bardet-Biedl syndrome proteins in the mammalian cochlea suggest noncentrosomal functions. J. Comp. Neurol. 514, 174–188 (2009).

  25. 25.

    et al. Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals. J. Neurosci. 26, 5265–5275 (2006).

  26. 26.

    et al. Asymmetric distribution of prickle-like 2 reveals an early underlying polarization of vestibular sensory epithelia in the inner ear. J. Neurosci. 27, 3139–3147 (2007).

  27. 27.

    , , & PAR proteins regulate microtubule dynamics at the cell cortex in C. elegans. Curr. Biol. 13, 707–714 (2003).

  28. 28.

    & Determination of the cleavage plane in early C. elegans embryos. Annu. Rev. Genet. 42, 389–411 (2008).

  29. 29.

    , , , & Heterotrimeric G-proteins interact directly with cytoskeletal components to modify microtubule-dependent cellular processes. Neurosignals 17, 100–108 (2009).

  30. 30.

    et al. Cortical dynein controls microtubule dynamics to generate pulling forces that position microtubule asters. Cell 148, 502–514 (2012).

  31. 31.

    et al. BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc. Natl Acad. Sci. USA 107, 1488–1493 (2010).

  32. 32.

    et al. Tubby is required for trafficking G protein-coupled receptors to neuronal cilia. Cilia 1, 21 (2012).

  33. 33.

    et al. Mouse gene knockout and knockin strategies in application to alpha subunits of Gi/Go family of G proteins. Methods Enzymol. 344, 277–298 (2002).

  34. 34.

    et al. Galphai2 is the essential Galphai protein in immune complex-induced lung disease. J. Immunol. 190, 324–333 (2013).

  35. 35.

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

  36. 36.

    , & Detection of planar polarity proteins in mammalian cochlea. Methods Mol. Biol. 468, 207–219 (2008).

  37. 37.

    , , , & Posttranslational modification of Galphao1 generates Galphao3, an abundant G protein in brain. Proc. Natl Acad. Sci. USA 96, 1327–1332 (1999).

  38. 38.

    et al. Molecular characterisation of endogenous vangl2/vangl1 heteromeric protein complexes. PLoS ONE 7, e46213 (2012).

  39. 39.

    et al. mPins modulates PSD-95 and SAP102 trafficking and influences NMDA receptor surface expression. Nat. Cell Biol. 7, 1179–1190 (2005).

Download references


We thank the animal and genotyping facilities’ members of the Neurocentre for technical assistance, notably H. Doat and D. Gonzales. We also thank the entire team of the Bordeaux Imaging Center (BIC) for the constant technical assistance, notably P. Legros, S. Marais and C. Poujol. We thank P. Beales (UCL, UK) for the Mkks mutants. We thank L. Mays (Tubingen, Germany) for critical reading of the manuscript, and F. Schweisguth (Paris, France) and J. Raff (Oxford, UK) for thoughtful discussions. We apologize to all whose relevant work could not be cited.

This research was supported by an INSERM grant to M.M. and N.S., the Conseil Regional d’Aquitaine Neurocampus program, La Fondation pour la Recherche Medicale (M.M., N.S., J.E., A-C.L.), ANR-08-MNPS-040-01 (M.M.), the European Commission Coordination Action ENINET (LSHM-CT-2005-19063; N.S. and M.M.), Ligue Nationale Contre le Cancer (Label 2010, J-P.B.), EUCAAD (FP7 program, J-P.B.), Fondation ARC pour la Recherche sur le Cancer (B.N., E.B.), the Deutsche Forschungsgemeinschaft (DFG; B.N., S.B-H.), the Intramural Research Program of the NIH (Project Z01-ES-101643 to L.B.), the European FP7 program (HEALTH-F2-2008-200234, A.L.B.) and ANR (BLAN07-2-186738, A.L.B.).

Author information


  1. INSERM, Planar Polarity and Plasticity Group, Neurocentre Magendie, 33077 Bordeaux, France

    • Jerome Ezan
    • , Léa Lasvaux
    • , Aysegul Gezer
    • , Nathalie Sans
    •  & Mireille Montcouquiol
  2. Université Bordeaux, Neurocentre Magendie, Bordeaux 33077, France

    • Jerome Ezan
    • , Léa Lasvaux
    • , Aysegul Gezer
    • , Nathalie Sans
    •  & Mireille Montcouquiol
  3. Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, 72074 Tübingen, Germany

    • Ana Novakovic
    • , Sandra Beer-Hammer
    •  & Bernd Nürnberg
  4. Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Helen May-Simera
  5. INSERM U1068, CRCM, 13009 Marseille, France

    • Edwige Belotti
    • , Anne-Catherine Lhoumeau
    •  & Jean-Paul Borg
  6. CNRS UMR7258, CRCM, 13009 Marseille, France

    • Edwige Belotti
    • , Anne-Catherine Lhoumeau
    •  & Jean-Paul Borg
  7. Institut Paoli-Calmettes, 13009 Marseille, France

    • Edwige Belotti
    • , Anne-Catherine Lhoumeau
    •  & Jean-Paul Borg
  8. Aix-Marseille Université, 13007 Marseille, France

    • Edwige Belotti
    • , Anne-Catherine Lhoumeau
    •  & Jean-Paul Borg
  9. Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health/Department of Health and Human Services, Durham, North Carolina 27709, USA

    • Lutz Birnbaumer
  10. CNRS, UMR 7288, Developmental Biology Institute of Marseille Luminy (IBDML), case 907, 13288 Marseille, cedex 09, France

    • André Le Bivic
  11. Aix-Marseille Université, Developmental Biology Institute of Marseille Luminy (IBDML), 13288 Marseille, France

    • André Le Bivic


  1. Search for Jerome Ezan in:

  2. Search for Léa Lasvaux in:

  3. Search for Aysegul Gezer in:

  4. Search for Ana Novakovic in:

  5. Search for Helen May-Simera in:

  6. Search for Edwige Belotti in:

  7. Search for Anne-Catherine Lhoumeau in:

  8. Search for Lutz Birnbaumer in:

  9. Search for Sandra Beer-Hammer in:

  10. Search for Jean-Paul Borg in:

  11. Search for André Le Bivic in:

  12. Search for Bernd Nürnberg in:

  13. Search for Nathalie Sans in:

  14. Search for Mireille Montcouquiol in:


M.M., J.E. and N.S. designed and carried out experiments, analysed data and wrote the paper. A.G. and L.L. carried out immunocytochemistry on cochleae, cultures and western blots. L.B., B.N., S.B-H., A.N. and A.L.B. generated and provided the G-protein mutant and G-protein antibodies, and carried out the characterization of the Go-protein antibody. E.B., A-C.L. and J-P.B. generated the rat anti-Vangl2 monoclonal antibody and PTK7-deficient mice. J-P.B., S.B-H., B.N. and A.L.B. provided experimental and conceptual advice and edited the manuscript. All authors discussed the results and implications and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mireille Montcouquiol.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Information

About this article

Publication history






Further reading