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  • Review Article
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Cellular signalling by primary cilia in development, organ function and disease

Abstract

Primary cilia project in a single copy from the surface of most vertebrate cell types; they detect and transmit extracellular cues to regulate diverse cellular processes during development and to maintain tissue homeostasis. The sensory capacity of primary cilia relies on the coordinated trafficking and temporal localization of specific receptors and associated signal transduction modules in the cilium. The canonical Hedgehog (HH) pathway, for example, is a bona fide ciliary signalling system that regulates cell fate and self-renewal in development and tissue homeostasis. Specific receptors and associated signal transduction proteins can also localize to primary cilia in a cell type-dependent manner; available evidence suggests that the ciliary constellation of these proteins can temporally change to allow the cell to adapt to specific developmental and homeostatic cues. Consistent with important roles for primary cilia in signalling, mutations that lead to their dysfunction underlie a pleiotropic group of diseases and syndromic disorders termed ciliopathies, which affect many different tissues and organs of the body. In this Review, we highlight central mechanisms by which primary cilia coordinate HH, G protein-coupled receptor, WNT, receptor tyrosine kinase and transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP) signalling and illustrate how defects in the balanced output of ciliary signalling events are coupled to developmental disorders and disease progression.

Key points

  • Primary cilia emanate in a single copy from the centrosomal mother centriole (basal body) at the surface of most vertebrate cell types.

  • Primary cilia possess a unique lipid and receptor composition and detect and convey extracellular cues to control cellular processes during development and in tissue homeostasis.

  • Current evidence suggests that primary cilia coordinate a variety of signalling pathways, including those regulated by Hedgehog (HH), G protein-coupled receptors (GPCRs), WNT, receptor tyrosine kinases (RTKs) and transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP), to control developmental processes, tissue plasticity and organ function.

  • The ability of primary cilia to balance the output of cellular signalling is dynamic and relies on the differentiation state and microenvironment of the cell.

  • Dysfunction of primary cilia underlies a pleiotropic group of diseases and syndromic disorders termed ciliopathies, affecting many different organs in the body.

  • Mechanistic insight into ciliary coordination of spatiotemporal signalling networks is critical for understanding the aetiology of ciliopathies and for the discovery of novel ciliopathy disease genes and drug targets.

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Fig. 1: Overview of primary cilia, cellular signalling and ciliopathies.
Fig. 2: Overview of canonical Hedgehog signalling in primary cilia.
Fig. 3: Overview of ciliary GPCR signalling.
Fig. 4: Overview of ciliary transition zone and basal body modulation of WNT signalling.
Fig. 5: Overview of ciliary PDGFRα, insulin and IGF1 signalling.
Fig. 6: Overview of ciliary TGFβ/BMP signalling.

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References

  1. Satir, P. & Christensen, S. T. Overview of structure and function of mammalian cilia. Annu. Rev. Physiol. 69, 377–400 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Kenny, T. D. & Beales, P. L. (eds) Ciliopathies: A Reference for Clinicians (Oxford Univ. Press, 2014).

  3. Heydeck, W., Fievet, L., Davis, E. E. & Katsanis, N. The complexity of the cilium: spatiotemporal diversity of an ancient organelle. Curr. Opin. Cell Biol. 55, 139–149 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sorokin, S. Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells. J. Cell Biol. 15, 363–377 (1962).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sorokin, S. P. Reconstructions of centriole formation and ciliogenesis in mammalian lungs. J. Cell Sci. 3, 207–230 (1968).

    CAS  PubMed  Google Scholar 

  6. Meunier, A. & Azimzadeh, J. Multiciliated cells in animals. Cold Spring Harb. Perspect. Biol. 8, a028233 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Avasthi, P. & Marshall, W. F. Stages of ciliogenesis and regulation of ciliary length. Differentiation 83, S30–42 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Broekhuis, J. R., Leong, W. Y. & Jansen, G. Regulation of cilium length and intraflagellar transport. Int. Rev. Cell. Mol. Biol. 303, 101–138 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Tucker, R. W., Pardee, A. B. & Fujiwara, K. Centriole ciliation is related to quiescence and DNA synthesis in 3T3 cells. Cell 17, 527–535 (1979).

    Article  CAS  PubMed  Google Scholar 

  10. Rieder, C. L., Jensen, C. G. & Jensen, L. C. The resorption of primary cilia during mitosis in a vertebrate (PtK1) cell line. J. Ultrastruct. Res. 68, 173–185 (1979).

    Article  CAS  PubMed  Google Scholar 

  11. Tucker, R. W., Scher, C. D. & Stiles, C. D. Centriole deciliation associated with the early response of 3T3 cells to growth factors but not to SV40. Cell 18, 1065–1072 (1979).

    Article  CAS  PubMed  Google Scholar 

  12. Pugacheva, E. N., Jablonski, S. A., Hartman, T. R., Henske, E. P. & Golemis, E. A. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129, 1351–1363 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Spalluto, C., Wilson, D. I. & Hearn, T. Evidence for reciliation of RPE1 cells in late G1 phase, and ciliary localisation of cyclin B1. FEBS Open Bio 3, 334–340 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ford, M. J. et al. A cell/cilia cycle biosensor for single-cell kinetics reveals persistence of cilia after G1/S transition is a general property in cells and mice. Dev. Cell 47, 509–523 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Das, R. M. & Storey, K. G. Apical abscission alters cell polarity and dismantles the primary cilium during neurogenesis. Science 343, 200–204 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. McDermott, K. M., Liu, B. Y., Tlsty, T. D. & Pazour, G. J. Primary cilia regulate branching morphogenesis during mammary gland development. Curr. Biol. 20, 731–737 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Blitzer, A. L. et al. Primary cilia dynamics instruct tissue patterning and repair of corneal endothelium. Proc. Natl Acad. Sci. USA 108, 2819–2824 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bangs, F. K., Schrode, N., Hadjantonakis, A. K. & Anderson, K. V. Lineage specificity of primary cilia in the mouse embryo. Nat. Cell Biol. 17, 113–122 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. May-Simera, H. L. et al. Primary cilium-mediated retinal pigment epithelium maturation is disrupted in ciliopathy patient cells. Cell Rep. 22, 189–205 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Iomini, C., Tejada, K., Mo, W., Vaananen, H. & Piperno, G. Primary cilia of human endothelial cells disassemble under laminar shear stress. J. Cell Biol. 164, 811–817 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Garcia-Gonzalo, F. R. & Reiter, J. F. Open sesame: how transition fibers and the transition zone control ciliary composition. Cold Spring Harb. Perspect. Biol. 9, a028134 (2016).

    Article  CAS  Google Scholar 

  22. Sung, C. H. & Leroux, M. R. The roles of evolutionarily conserved functional modules in cilia-related trafficking. Nat. Cell Biol. 15, 1387–1397 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Morthorst, S. K., Christensen, S. T. & Pedersen, L. B. Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins. FEBS J. 285, 4535–4564 (2018).

    Article  CAS  PubMed  Google Scholar 

  24. Lechtreck, K. F. IFT-cargo interactions and protein transport in cilia. Trends Biochem. Sci. 40, 765–778 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Taschner, M. & Lorentzen, E. The intraflagellar transport machinery. Cold Spring Harb. Perspect. Biol. 8, a028092 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Wood, C. R., Huang, K., Diener, D. R. & Rosenbaum, J. L. The cilium secretes bioactive ectosomes. Curr. Biol. 23, 906–911 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Cao, M. et al. Uni-directional ciliary membrane protein trafficking by a cytoplasmic retrograde IFT motor and ciliary ectosome shedding. eLife 4, e05242 (2015).

    Article  PubMed Central  CAS  Google Scholar 

  28. Nager, A. R. et al. An actin network dispatches ciliary GPCRs into extracellular vesicles to modulate signaling. Cell 168, 252–263 (2017).

    Article  CAS  PubMed  Google Scholar 

  29. Reiter, J. F. & Leroux, M. R. Genes and molecular pathways underpinning ciliopathies. Nat. Rev. Mol. Cell Biol. 18, 533–547 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pedersen, L. B. & Rosenbaum, J. L. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr. Top. Dev. Biol. 85, 23–61 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Prevo, B., Scholey, J. M. & Peterman, E. J. G. Intraflagellar transport: mechanisms of motor action, cooperation, and cargo delivery. FEBS J. 284, 2905–2931 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kozminski, K. G., Johnson, K. A., Forscher, P. & Rosenbaum, J. L. A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc. Natl Acad. Sci. USA 90, 5519–5523 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Walther, Z., Vashishtha, M. & Hall, J. L. The Chlamydomonas FLA10 gene encodes a novel kinesin-homologous protein. J. Cell Biol. 126, 175–188 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Kozminski, K. G., Beech, P. L. & Rosenbaum, J. L. The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane. J. Cell Biol. 131, 1517–1527 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Vashishtha, M., Walther, Z. & Hall, J. L. The kinesin-homologous protein encoded by the Chlamydomonas FLA10 gene is associated with basal bodies and centrioles. J. Cell Sci. 109, 541–549 (1996).

    CAS  PubMed  Google Scholar 

  36. Pazour, G. J., Wilkerson, C. G. & Witman, G. B. A dynein light chain is essential for retrograde particle movement in intraflagellar transport (IFT). J. Cell Biol. 141, 979–992 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pazour, G. J., Dickert, B. L. & Witman, G. B. The DHC1b (DHC2) isoform of cytoplasmic dynein is required for flagellar assembly. J. Cell Biol. 144, 473–481 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Porter, M. E., Bower, R., Knott, J. A., Byrd, P. & Dentler, W. Cytoplasmic dynein heavy chain 1b is required for flagellar assembly in Chlamydomonas. Mol. Biol. Cell 10, 693–712 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Verhey, K. J., Dishinger, J. & Kee, H. L. Kinesin motors and primary cilia. Biochem. Soc. Trans. 39, 1120–1125 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ou, G., Blacque, O. E., Snow, J. J., Leroux, M. R. & Scholey, J. M. Functional coordination of intraflagellar transport motors. Nature 436, 583–587 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Snow, J. J. et al. Two anterograde intraflagellar transport motors cooperate to build sensory cilia on C. elegans neurons. Nat. Cell Biol. 6, 1109–1113 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Zhao, C., Omori, Y., Brodowska, K., Kovach, P. & Malicki, J. Kinesin-2 family in vertebrate ciliogenesis. Proc. Natl Acad. Sci. USA 109, 2388–2393 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Prevo, B., Mangeol, P., Oswald, F., Scholey, J. M. & Peterman, E. J. Functional differentiation of cooperating kinesin-2 motors orchestrates cargo import and transport in C. elegans cilia. Nat. Cell Biol. 17, 1536–1545 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Cole, D. G. et al. Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J. Cell Biol. 141, 993–1008 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Piperno, G. & Mead, K. Transport of a novel complex in the cytoplasmic matrix of Chlamydomonas flagella. Proc. Natl Acad. Sci. USA 94, 4457–4462 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rosenbaum, J. L. & Witman, G. B. Intraflagellar transport. Nat. Rev. Mol. Cell Biol. 3, 813–825 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Taschner, M., Kotsis, F., Braeuer, P., Kuehn, E. W. & Lorentzen, E. Crystal structures of IFT70/52 and IFT52/46 provide insight into intraflagellar transport B core complex assembly. J. Cell Biol. 207, 269–282 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bhogaraju, S., Engel, B. D. & Lorentzen, E. Intraflagellar transport complex structure and cargo interactions. Cilia 2, 10 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Toropova, K., Mladenov, M. & Roberts, A. J. Intraflagellar transport dynein is autoinhibited by trapping of its mechanical and track-binding elements. Nat. Struct. Mol. Biol. 24, 461–468 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Funabashi, T., Katoh, Y., Okazaki, M., Sugawa, M. & Nakayama, K. Interaction of heterotrimeric kinesin-II with IFT-B-connecting tetramer is crucial for ciliogenesis. J. Cell Biol. 217, 2867–2876 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mohamed, M. A. A., Stepp, W. L. & Okten, Z. Reconstitution reveals motor activation for intraflagellar transport. Nature 557, 387–391 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liang, Y., Zhu, X., Wu, Q. & Pan, J. Ciliary length sensing regulates IFT entry via changes in FLA8/KIF3B phosphorylation to control ciliary assembly. Curr. Biol. 28, 2429–2435 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Jordan, M. A., Diener, D. R., Stepanek, L. & Pigino, G. The cryo-EM structure of intraflagellar transport trains reveals how dynein is inactivated to ensure unidirectional anterograde movement in cilia. Nat. Cell Biol. 20, 1250–1255 (2018).

    Article  CAS  PubMed  Google Scholar 

  54. Perkins, L. A., Hedgecock, E. M., Thomson, J. N. & Culotti, J. G. Mutant sensory cilia in the nematode Caenorhabditis elegans. Dev. Biol. 117, 456–487 (1986).

    Article  CAS  PubMed  Google Scholar 

  55. Pedersen, L. B. et al. Chlamydomonas IFT172 is encoded by FLA11, interacts with CrEB1, and regulates IFT at the flagellar tip. Curr. Biol. 15, 262–266 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Qin, H. et al. Intraflagellar transport is required for the vectorial movement of TRPV channels in the ciliary membrane. Curr. Biol. 15, 1695–1699 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Mukhopadhyay, S. et al. TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia. Genes Dev. 24, 2180–2193 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Behal, R. H. et al. Subunit interactions and organization of the Chlamydomonas reinhardtii intraflagellar transport complex A proteins. J. Biol. Chem. 287, 11689–11703 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Liem, K. F. Jr. et al. The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking. J. Cell Biol. 197, 789–800 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Keady, B. T. et al. IFT25 links the signal-dependent movement of Hedgehog components to intraflagellar transport. Dev. Cell 22, 940–951 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Eguether, T. et al. IFT27 links the BBSome to IFT for maintenance of the ciliary signaling compartment. Dev. Cell 31, 279–290 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bhogaraju, S. et al. Molecular basis of tubulin transport within the cilium by IFT74 and IFT81. Science 341, 1009–1012 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Eguether, T., Cordelieres, F. P. & Pazour, G. J. Intraflagellar transport is deeply integrated in hedgehog signaling. Mol. Biol. Cell 29, 1178–1189 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Mourão, A., Christensen, S. T. & Lorentzen, E. The intraflagellar transport machinery in ciliary signaling. Curr. Opin. Struct. Biol. 41, 98–108 (2016).

    Article  PubMed  CAS  Google Scholar 

  65. Badgandi, H. B., Hwang, S. H., Shimada, I. S., Loriot, E. & Mukhopadhyay, S. Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins. J. Cell Biol. 216, 743–760 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Takahara, M. et al. Ciliopathy-associated mutations of IFT122 impair ciliary protein trafficking but not ciliogenesis. Hum. Mol. Genet. 27, 516–528 (2018).

    Article  CAS  PubMed  Google Scholar 

  67. Hirano, T., Katoh, Y. & Nakayama, K. Intraflagellar transport-A complex mediates ciliary entry and retrograde trafficking of ciliary G protein-coupled receptors. Mol. Biol. Cell 28, 429–439 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fu, W., Wang, L., Kim, S., Li, J. & Dynlacht, B. D. Role for the IFT-A complex in selective transport to the primary cilium. Cell Rep. 17, 1505–1517 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Caparrós-Martín, J. A. et al. Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium. Hum. Mol. Genet. 24, 4126–4137 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Boubakri, M. et al. Loss of ift122, a retrograde intraflagellar transport (IFT) complex component, leads to slow, progressive photoreceptor degeneration due to inefficient opsin transport. J. Biol. Chem. 291, 24465–24474 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Nachury, M. V. et al. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129, 1201–1213 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Lechtreck, K. F. et al. The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J. Cell Biol. 187, 1117–1132 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Berbari, N. F., Lewis, J. S., Bishop, G. A., Askwith, C. C. & Mykytyn, K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc. Natl Acad. Sci. USA 105, 4242–4246 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Loktev, A. V. & Jackson, P. K. Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia. Cell Rep. 5, 1316–1329 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Jin, H. et al. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141, 1208–1219 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lechtreck, K. F. et al. Cycling of the signaling protein phospholipase D through cilia requires the BBSome only for the export phase. J. Cell Biol. 201, 249–261 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nachury, M. V. The molecular machines that traffic signaling receptors into and out of cilia. Curr. Opin. Cell Biol. 51, 124–131 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wingfield, J. L., Lechtreck, K.-F. & Lorentzen, E. Trafficking of ciliary membrane proteins by the intraflagellar transport/BBSome machinery. Essays Biochem. 62, 753–763 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Pazour, G. J. et al. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J. Cell Biol. 151, 709–718 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Moyer, J. et al. Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice. Science 264, 1329–1333 (1994).

    Article  CAS  PubMed  Google Scholar 

  81. Barr, M. M. & Sternberg, P. W. A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature 401, 386–389 (1999).

    CAS  PubMed  Google Scholar 

  82. Yoder, B. K., Hou, X. & Guay-Woodford, L. M. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J. Am. Soc. Nephrol. 13, 2508–2516 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Pazour, G. J., San Agustin, J. T., Follit, J. A., Rosenbaum, J. L. & Witman, G. B. Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr. Biol. 12, R378–R380 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Nauli, S. M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33, 129–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Ma, M., Gallagher, A. R. & Somlo, S. Ciliary mechanisms of cyst formation in polycystic kidney disease. Cold Spring Harb. Perspect. Biol. 9, a028209 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Norris, D. P. Cilia, calcium and the basis of left-right asymmetry. BMC Biol. 10, 102 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Pennekamp, P. et al. The ion channel polycystin-2 is required for left-right axis determination in mice. Curr. Biol. 12, 938–943 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Bataille, S. et al. Association of PKD2 (polycystin 2) mutations with left-right laterality defects. Am. J. Kidney Dis. 58, 456–460 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Qian, F. et al. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat. Genet. 16, 179–183 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Delling, M. et al. Primary cilia are not calcium-responsive mechanosensors. Nature 531, 656–660 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Norris, D. P. & Jackson, P. K. Cell biology: calcium contradictions in cilia. Nature 531, 582–583 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Shen, P. S. et al. The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs. Cell 167, 763–773 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Grieben, M. et al. Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). Nat. Struct. Mol. Biol. 24, 114–122 (2017).

    Article  CAS  PubMed  Google Scholar 

  94. Liu, X. et al. Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium. eLife 7, e33183 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Su, Q. et al. Structure of the human PKD1-PKD2 complex. Science 361, eaat9819 (2018).

    Article  PubMed  CAS  Google Scholar 

  96. Briscoe, J. & Thérond, P. P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 14, 416 (2013).

    Article  PubMed  CAS  Google Scholar 

  97. Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Goetz, S. C. & Anderson, K. V. The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11, 331–344 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yue, S. et al. Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception. eLife 3, e02555 (2014).

    Article  PubMed Central  CAS  Google Scholar 

  100. Schou, K. B. et al. KIF13B establishes a CAV1-enriched microdomain at the ciliary transition zone to promote Sonic hedgehog signalling. Nat. Commun. 8, 14177 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Scheidel, N., Kennedy, J. & Blacque, O. E. Endosome maturation factors Rabenosyn-5/VPS45 and caveolin-1 regulate ciliary membrane and polycystin-2 homeostasis. EMBO J. 37, e98248 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  102. Corbit, K. C. et al. Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018–1021 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Rohatgi, R., Milenkovic, L. & Scott, M. P. Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372–376 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Niewiadomski, P. et al. Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling. Cell Rep. 6, 168–181 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Mukhopadhyay, S. & Rohatgi, R. G-Protein-coupled receptors, Hedgehog signaling and primary cilia. Semin. Cell Dev. Biol. 33, 63–72 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Bitgood, M. J. & McMahon, A. P. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol. 172, 126–138 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Carballo, G. B., Honorato, J. R., de Lopes, G. P. F. & Spohr, T. C. L. S. E. A highlight on Sonic hedgehog pathway. Cell Commun. Signal. 16, 11 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Bijlsma, M. F. & Roelink, H. Non-cell-autonomous signaling by Shh in tumors: challenges and opportunities for therapeutic targets. Expert Opin. Ther. Targets 14, 693–702 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yuan, X. et al. Ciliary IFT80 balances canonical versus non-canonical hedgehog signalling for osteoblast differentiation. Nat. Commun. 7, 11024–11024 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bijlsma, M. F., Damhofer, H. & Roelink, H. Hedgehog-stimulated chemotaxis is mediated by smoothened located outside the primary cilium. Sci. Signal. 5, ra60 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Ho Wei, L., Arastoo, M., Georgiou, I., Manning, D. R. & Riobo-Del Galdo, N. A. Activation of the Gi protein-RHOA axis by non-canonical Hedgehog signaling is independent of primary cilia. PLOS ONE 13, e0203170 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Gong, X. et al. Structural basis for the recognition of Sonic Hedgehog by human Patched1. Science 361, eaas8935 (2018).

    Article  PubMed  CAS  Google Scholar 

  113. Qi, X., Schmiege, P., Coutavas, E., Wang, J. & Li, X. Structures of human Patched and its complex with native palmitoylated sonic hedgehog. Nature 560, 128–132 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Huang, P. et al. Structural basis of Smoothened activation in Hedgehog signaling. Cell 174, 312–324 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Nachtergaele, S. et al. Oxysterols are allosteric activators of the oncoprotein Smoothened. Nat. Chem. Biol. 8, 211–220 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang, Y. et al. Structural basis for cholesterol transport-like activity of the hedgehog receptor Patched. Cell 175, 1352–1364 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dorn, K. V., Hughes, C. E. & Rohatgi, R. A. Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev. Cell 23, 823–835 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Singh, J., Wen, X. & Scales, S. J. The orphan G protein-coupled receptor Gpr175 (Tpra40) enhances Hedgehog signaling by modulating cAMP levels. J. Biol. Chem. 290, 29663–29675 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Haycraft, C. J. et al. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLOS Genet. 1, e53 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Jiang, J. & Struhl, G. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391, 493–496 (1998).

    Article  CAS  PubMed  Google Scholar 

  121. Tempe, D., Casas, M., Karaz, S., Blanchet-Tournier, M. F. & Concordet, J. P. Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. Mol. Cell. Biol. 26, 4316–4326 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Pan, Y. & Wang, B. A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. J. Biol. Chem. 282, 10846–10852 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Wang, B., Fallon, J. F. & Beachy, P. A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423–434 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Mukhopadhyay, S. et al. The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell 152, 210–223 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Humke, E. W., Dorn, K. V., Milenkovic, L., Scott, M. P. & Rohatgi, R. The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins. Genes Dev. 24, 670–682 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Jia, J. et al. Suppressor of Fused inhibits mammalian Hedgehog signaling in the absence of cilia. Dev. Biol. 330, 452–460 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Tuson, M., He, M. & Anderson, K. V. Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development 138, 4921–4930 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Svard, J. et al. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev. Cell 10, 187–197 (2006).

    Article  PubMed  CAS  Google Scholar 

  129. Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997).

    Article  CAS  PubMed  Google Scholar 

  130. Norman, R. X. et al. Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling. Hum. Mol. Genet. 18, 1740–1754 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Patterson, V. L. et al. Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway. Hum. Mol. Genet. 18, 1719–1739 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Qin, J., Lin, Y., Norman, R. X., Ko, H. W. & Eggenschwiler, J. T. Intraflagellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components. Proc. Natl Acad. Sci. USA 108, 1456–1461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ocbina, P. J. R., Eggenschwiler, J. T., Moskowitz, I. & Anderson, K. V. Complex interactions between genes controlling trafficking in primary cilia. Nat. Genet. 43, 547–553 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Hwang, S. H. & Mukhopadhyay, S. G-Protein-coupled receptors and localized signaling in the primary cilium during ventral neural tube patterning. Birth Defects Res. A Clin. Mol. Teratol 103, 12–19 (2015).

    Article  CAS  Google Scholar 

  135. Pusapati, G. V. et al. G protein-coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog. Sci. Signal. 11, eaao5749 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Hwang, S. H. et al. The G protein-coupled receptor Gpr161 regulates forelimb formation, limb patterning and skeletal morphogenesis in a primary cilium-dependent manner. Development 145, dev154054 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Shimada, I. S. et al. Basal suppression of the Sonic Hedgehog pathway by the G-protein-coupled receptor Gpr161 restricts medulloblastoma pathogenesis. Cell Rep. 22, 1169–1184 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. He, M. et al. The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment. Nat. Cell Biol. 16, 663–672 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Liem, K. F. Jr., He, M., Ocbina, P. J. & Anderson, K. V. Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc. Natl Acad. Sci. USA 106, 13377–13382 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Pal, K. et al. Smoothened determines β-arrestin-mediated removal of the G protein-coupled receptor Gpr161 from the primary cilium. J. Cell Biol. 212, 861–875 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Garcia-Gonzalo, F. R. et al. Phosphoinositides regulate ciliary protein trafficking to modulate Hedgehog signaling. Dev. Cell 34, 400–409 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Chavez, M. et al. Modulation of ciliary phosphoinositide content regulates trafficking and Sonic Hedgehog signaling output. Dev. Cell 34, 338–350 (2015).

    Article  CAS  PubMed  Google Scholar 

  143. Wong, W. & Scott, J. D. AKAP signalling complexes: focal points in space and time. Nat. Rev. Mol. Cell Biol. 5, 959–970 (2004).

    Article  CAS  PubMed  Google Scholar 

  144. Bachmann, V. A. et al. Gpr161 anchoring of PKA consolidates GPCR and cAMP signaling. Proc. Natl Acad. Sci. USA 113, 7786–7791 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Mick, D. U. et al. Proteomics of primary cilia by proximity labeling. Dev. Cell 35, 497–512 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Choi, Y. H. et al. Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases. Proc. Natl Acad. Sci. USA 108, 10679–10684 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Bishop, G. A., Berbari, N. F., Lewis, J. & Mykytyn, K. Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. J. Comp. Neurol. 505, 562–571 (2007).

    Article  PubMed  Google Scholar 

  148. Vuolo, L., Herrera, A., Torroba, B., Menendez, A. & Pons, S. Ciliary adenylyl cyclases control the Hedgehog pathway. J. Cell Sci. 128, 2928–2937 (2015).

    Article  CAS  PubMed  Google Scholar 

  149. Fredriksson, R., Lagerstrom, M. C., Lundin, L. G. & Schioth, H. B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63, 1256–1272 (2003).

    Article  CAS  PubMed  Google Scholar 

  150. Pandy-Szekeres, G. et al. GPCRdb in 2018: adding GPCR structure models and ligands. Nucleic Acids Res. 46, D440–D446 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schioth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 16, 829–842 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Hilger, D., Masureel, M. & Kobilka, B. K. Structure and dynamics of GPCR signaling complexes. Nat. Struct. Mol. Biol. 25, 4–12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Eichel, K. & von Zastrow, M. Subcellular organization of GPCR signaling. Trends Pharmacol. Sci. 39, 200–208 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Mykytyn, K. & Askwith, C. G-protein-coupled receptor signaling in cilia. Cold Spring Harb. Perspect. Biol. 9, a028183 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  155. Schou, K. B., Pedersen, L. B. & Christensen, S. T. Ins and outs of GPCR signaling in primary cilia. EMBO Rep. 16, 1099–1113 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Tabibian, J. H., Masyuk, A. I., Masyuk, T. V., O’Hara, S. P. & LaRusso, N. F. Physiology of cholangiocytes. Compr. Physiol. 3, 541–565 (2013).

    PubMed  Google Scholar 

  157. Masyuk, A. I. et al. Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G725–G734 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Masyuk, T. V., Masyuk, A. I. & LaRusso, N. F. TGR5 in the cholangiociliopathies. Dig. Dis. 33, 420–425 (2015).

    Article  PubMed  Google Scholar 

  159. Keitel, V., Ullmer, C. & Haussinger, D. The membrane-bound bile acid receptor TGR5 (Gpbar-1) is localized in the primary cilium of cholangiocytes. Biol. Chem. 391, 785–789 (2010).

    Article  CAS  PubMed  Google Scholar 

  160. Masyuk, A. I. et al. Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G1013–G1024 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Cramer, M. T. & Guay-Woodford, L. M. Cystic kidney disease: a primer. Adv. Chronic Kidney Dis. 22, 297–305 (2015).

    Article  PubMed  Google Scholar 

  162. Jin, X. et al. Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli. Cell. Mol. Life Sci. 71, 2165–2178 (2014).

    Article  CAS  PubMed  Google Scholar 

  163. Upadhyay, V. S. et al. Roles of dopamine receptor on chemosensory and mechanosensory primary cilia in renal epithelial cells. Front. Physiol. 5, 72 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Raychowdhury, M. K. et al. Vasopressin receptor-mediated functional signaling pathway in primary cilia of renal epithelial cells. Am. J. Physiol. Renal Physiol. 296, F87–F97 (2009).

    Article  CAS  PubMed  Google Scholar 

  165. Torres, V. E. et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N. Engl. J. Med. 377, 1930–1942 (2017).

    Article  CAS  PubMed  Google Scholar 

  166. Wang, C. Y., Tsai, H. L., Syu, J. S., Chen, T. Y. & Su, M. T. Primary cilium-regulated EG-VEGF signaling facilitates trophoblast invasion. J. Cell. Physiol. 232, 1467–1477 (2017).

    Article  CAS  PubMed  Google Scholar 

  167. Guemez-Gamboa, A., Coufal, N. G. & Gleeson, J. G. Primary cilia in the developing and mature brain. Neuron 82, 511–521 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Green, J. A. et al. Recruitment of β-arrestin into neuronal cilia modulates somatostatin receptor subtype 3 ciliary localization. Mol. Cell. Biol. 36, 223–235 (2016).

    CAS  PubMed  Google Scholar 

  169. Domire, J. S. et al. Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet-Biedl syndrome proteins. Cell. Mol. Life Sci. 68, 2951–2960 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Marin, O. Interneuron dysfunction in psychiatric disorders. Nat. Rev. Neurosci. 13, 107–120 (2012).

    Article  CAS  PubMed  Google Scholar 

  172. Guo, J. et al. Primary cilia signaling shapes the development of interneuronal connectivity. Dev. Cell 42, 286–300 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Ye, F., Nager, A. R. & Nachury, M. V. BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone. J. Cell Biol. 217, 1847–1868 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Berbari, N. F. et al. Hippocampal and cortical primary cilia are required for aversive memory in mice. PLOS ONE 9, e106576 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Einstein, E. B. et al. Somatostatin signaling in neuronal cilia is critical for object recognition memory. J. Neurosci. 30, 4306–4314 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Liu, X. et al. β-arrestin-biased signaling mediates memory reconsolidation. Proc. Natl Acad. Sci. USA 112, 4483–4488 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Wang, Z., Phan, T. & Storm, D. R. The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia. J. Neurosci. 31, 5557–5561 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Berbari, N. F. et al. Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice. Proc. Natl Acad. Sci. USA 110, 7796–7801 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Davenport, J. R. et al. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr. Biol. 17, 1586–1594 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Farooqi, I. S. et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl. J. Med. 348, 1085–1095 (2003).

    Article  CAS  PubMed  Google Scholar 

  181. Siljee, J. E. et al. Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nat. Genet. 50, 180–185 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Loh, K., Herzog, H. & Shi, Y. C. Regulation of energy homeostasis by the NPY system. Trends Endocrinol. Metab. 26, 125–135 (2015).

    Article  CAS  PubMed  Google Scholar 

  183. Marion, S., Oakley, R. H., Kim, K. M., Caron, M. G. & Barak, L. S. A β-arrestin binding determinant common to the second intracellular loops of rhodopsin family G protein-coupled receptors. J. Biol. Chem. 281, 2932–2938 (2006).

    Article  CAS  PubMed  Google Scholar 

  184. Clevers, H. Wnt/β-catenin signaling in development and disease. Cell 127, 469–480 (2006).

    Article  CAS  PubMed  Google Scholar 

  185. Niehrs, C. The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol. 13, 767 (2012).

    Article  CAS  PubMed  Google Scholar 

  186. MacDonald, B. T. & He, X. Frizzled and LRP5/6 receptors for Wnt/β-catenin signaling. Cold Spring Harb. Perspect. Biol. 4, a007880 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Sineva, G. S. & Pospelov, V. A. in International Review of Cell and Molecular Biology Vol. 312 (ed. Jeon, K. W.) 53–78 (Academic Press, 2014).

  188. Kim, W., Kim, M. & Jho, E. H. Wnt/β-catenin signalling: from plasma membrane to nucleus. Biochem. J. 450, 9–21 (2013).

    Article  CAS  PubMed  Google Scholar 

  189. Green, J., Nusse, R. & van Amerongen, R. The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction. Cold Spring Harb. Perspect. Biol. 6, a009175 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Yang, Y. & Mlodzik, M. Wnt-Frizzled/planar cell polarity signaling: cellular orientation by facing the wind (Wnt). Annu. Rev. Cell Dev. Biol. 31, 623–646 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Berger, H., Wodarz, A. & Borchers, A. PTK7 faces the Wnt in development and disease. Front. Cell Dev. Biol. 5, 31 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Nishita, M. et al. Ror2/Frizzled complex mediates Wnt5a-induced AP-1 activation by regulating Dishevelled polymerization. Mol. Cell. Biol. 30, 3610–3619 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Witte, F. et al. Negative regulation of Wnt signaling mediated by CK1-phosphorylated Dishevelled via Ror2. FASEB J. 24, 2417–2426 (2010).

    Article  CAS  PubMed  Google Scholar 

  194. Corbit, K. C. et al. Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat. Cell Biol. 10, 70–76 (2008).

    Article  CAS  PubMed  Google Scholar 

  195. Zhang, B. et al. GSK3β-Dzip1-Rab8 cascade regulates ciliogenesis after mitosis. PLOS Biol. 13, e1002129 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Chen, Y. et al. Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of Smoothened. PLOS Biol. 9, e1001083 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Veland, I. R. et al. Inversin/Nephrocystin-2 is required for fibroblast polarity and directional cell migration. PLOS ONE 8, e60193 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Marion, V. et al. Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation. Proc. Natl Acad. Sci. USA 106, 1820–1825 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Lienkamp, S. et al. Inversin relays Frizzled-8 signals to promote proximal pronephros development. Proc. Natl Acad. Sci. USA 107, 20388–20393 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Ocbina, P. J. R., Tuson, M. & Anderson, K. V. Primary cilia are not required for normal canonical Wnt signaling in the mouse embryo. PLOS ONE 4, e6839 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Kim, M. et al. KIF3A binds to β-arrestin for suppressing Wnt/β-catenin signalling independently of primary cilia in lung cancer. Sci. Rep. 6, 32770 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Vuong, L. T., Mukhopadhyay, B. & Choi, K.-W. Kinesin-II recruits Armadillo and Dishevelled for Wingless signaling in Drosophila. Development 141, 3222–3232 (2014).

    Article  CAS  PubMed  Google Scholar 

  204. Huang, P. & Schier, A. F. Dampened Hedgehog signaling but normal Wnt signaling in zebrafish without cilia. Development 136, 3089–3098 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Oh, E. C. & Katsanis, N. Context-dependent regulation of Wnt signaling through the primary cilium. J. Am. Soc. Nephrol. 24, 10–18 (2013).

    Article  CAS  PubMed  Google Scholar 

  206. Lancaster, M. A. et al. Impaired Wnt–β-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy. Nat. Med. 15, 1046 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Lancaster, M. A., Schroth, J. & Gleeson, J. G. Subcellular spatial regulation of canonical Wnt signalling at the primary cilium. Nat. Cell Biol. 13, 700 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Lancaster, M. A. et al. Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome. Nat. Med. 17, 726 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Abdelhamed, Z. A. et al. The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway. Dis. Model. Mech. 8, 527–541 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Bergmann, C. et al. Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am. J. Hum. Genet. 82, 959–970 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Burcklé, C. et al. Control of the Wnt pathways by nephrocystin-4 is required for morphogenesis of the zebrafish pronephros. Hum. Mol. Genet. 20, 2611–2627 (2011).

    Article  PubMed  CAS  Google Scholar 

  212. Mahuzier, A. et al. Dishevelled stabilization by the ciliopathy protein Rpgrip1l is essential for planar cell polarity. J. Cell Biol. 198, 927–940 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Patnaik, S. R. et al. RPGR protein complex regulates proteasome activity and mediates store-operated calcium entry. Oncotarget 9, 23183–23197 (2018).

    PubMed  PubMed Central  Google Scholar 

  214. Borgal, L. et al. The ciliary protein nephrocystin-4 translocates the canonical Wnt regulator Jade-1 to the nucleus to negatively regulate β-catenin signaling. J. Biol. Chem. 287, 25370–25380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Chitalia, V. C. et al. Jade-1 inhibits Wnt signaling by ubiquitinating β-catenin and mediates Wnt pathway inhibition by pVHL. Nat. Cell Biol. 10, 1208–1216 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Gerhardt, C. et al. The transition zone protein Rpgrip1l regulates proteasomal activity at the primary cilium. J. Cell Biol. 210, 1027 (2015).

    Article  PubMed Central  CAS  Google Scholar 

  217. Gerdes, J. M. et al. Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nat. Genet. 39, 1350–1360 (2007).

    Article  CAS  PubMed  Google Scholar 

  218. Gerhardt, C., Leu, T., Lier, J. M. & Rüther, U. The cilia-regulated proteasome and its role in the development of ciliopathies and cancer. Cilia 5, 14 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Liu, Y. P. et al. Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators. J. Clin. Invest. 124, 2059–2070 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Hua, K. & Ferland, R. J. Primary cilia proteins: ciliary and extraciliary sites and functions. Cell. Mol. Life Sci. 75, 1521–1540 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor-tyrosine kinases. Cell 141, 1117–1134 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Crudden, C. et al. in International Review of Cell and Molecular Biology Vol. 339. (ed. Shukla, A. K.) 1–40 (Academic Press, 2018).

  223. Christensen, S. T., Clement, C. A., Satir, P. & Pedersen, L. B. Primary cilia and coordination of receptor tyrosine kinase (RTK) signalling. J. Pathol. 226, 172–184 (2012).

    Article  CAS  PubMed  Google Scholar 

  224. Christensen, S. T., Morthorst, S. K., Mogensen, J. B. & Pedersen, L. B. Primary cilia and coordination of receptor tyrosine kinase (RTK) and transforming growth factor beta (TGF-β) signaling. Cold Spring Harb. Perspect. Biol. 9, a028167 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  225. Ma, R. et al. PKD2 functions as an epidermal growth factor-activated plasma membrane channel. Mol. Cell. Biol. 25, 8285–8298 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Danilov, A. I. et al. Ultrastructural and antigenic properties of neural stem cells and their progeny in adult rat subventricular zone. Glia 57, 136–152 (2009).

    Article  PubMed  Google Scholar 

  227. Martin, L. et al. Constitutively-active FGFR3 disrupts primary cilium length and IFT20 trafficking in various chondrocyte models of achondroplasia. Hum. Mol. Genet. 27, 1–13 (2018).

    Article  CAS  PubMed  Google Scholar 

  228. Leitch, C. C. & Zaghloul, N. A. BBS4 is necessary for ciliary localization of TrkB receptor and activation by BDNF. PLOS ONE 9, e98687 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  229. Teilmann, S. C. & Christensen, S. T. Localization of the angiopoietin receptors Tie-1 and Tie-2 on the primary cilia in the female reproductive organs. Cell Biol. Int. 29, 340–346 (2005).

    Article  CAS  PubMed  Google Scholar 

  230. Kunova Bosakova, M. et al. Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies. Hum. Mol. Genet. 27, 1093–1105 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  231. Zhu, D., Shi, S., Wang, H. & Liao, K. Growth arrest induces primary-cilium formation and sensitizes IGF-1-receptor signaling during differentiation induction of 3T3-L1 preadipocytes. J. Cell Sci. 122, 2760–2768 (2009).

    Article  CAS  PubMed  Google Scholar 

  232. Dalbay, M. T., Thorpe, S. D., Connelly, J. T., Chapple, J. P. & Knight, M. M. Adipogenic differentiation of hMSCs is mediated by recruitment of IGF-1r onto the primary cilium associated with cilia elongation. Stem Cells 33, 1952–1961 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Yeh, C. et al. IGF-1 activates a cilium-localized non-canonical Gβγ signaling pathway that regulates cell cycle progression. Dev. Cell 26, 358–368 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Gabriel, E. et al. CPAP promotes timely cilium disassembly to maintain neural progenitor pool. EMBO J. 35, 803–819 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Wang, H. et al. Hsp90α forms a stable complex at the cilium neck for the interaction of signalling molecules in IGF-1 receptor signalling. J. Cell Sci. 128, 100–108 (2015).

    Article  CAS  PubMed  Google Scholar 

  236. Gerdes, J. M. et al. Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents. Nat. Commun. 5, 5308 (2014).

    Article  CAS  PubMed  Google Scholar 

  237. Volta, F. & Gerdes, J. M. The role of primary cilia in obesity and diabetes. Ann. NY Acad. Sci. 1391, 71–84 (2017).

    Article  PubMed  Google Scholar 

  238. Song, D. K., Choi, J. H. & Kim, M.-S. Primary cilia as a signaling platform for control of energy metabolism. Diabetes Metab. J. 42, 117–127 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Leibiger, B. et al. Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol. Cell 7, 559–570 (2001).

    Article  CAS  PubMed  Google Scholar 

  240. Heldin, C.-H., Lennartsson, J. & Westermark, B. Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. J. Intern. Med. 283, 16–44 (2018).

    Article  CAS  PubMed  Google Scholar 

  241. Schneider, L. et al. PDGFRαα signaling is regulated through the primary cilium in fibroblasts. Curr. Biol. 15, 1861–1866 (2005).

    Article  CAS  PubMed  Google Scholar 

  242. Vestergaard, M. L., Awan, A., Warzecha, C. B., Christensen, S. T. & Andersen, C. Y. in Human Embryonic Stem Cell Protocols (ed. Turksen, K.) 123–140 (Springer, NY, 2016).

  243. Noda, K., Kitami, M., Kitami, K., Kaku, M. & Komatsu, Y. Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development. Proc. Natl Acad. Sci. USA 113, E2589–E2597 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Gerhardt, C., Lier, J. M., Kuschel, S. & Rüther, U. The ciliary protein Ftm is required for ventricular wall and septal development. PLOS ONE 8, e57545 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Kopinke, D., Roberson, E. C. & Reiter, J. F. Ciliary Hedgehog signaling restricts injury-induced adipogenesis. Cell 170, 340–351 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Falcón-Urrutia, P., Carrasco, C. M., Lois, P., Palma, V. & Roth, A. D. Shh signaling through the primary cilium modulates rat oligodendrocyte differentiation. PLOS ONE 10, e0133567 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  247. Nielsen, B. S. et al. PDGFRβ and oncogenic mutant PDGFRα D842V promote disassembly of primary cilia through a PLCγ- and AURKA-dependent mechanism. J. Cell Sci. 128, 3543–3549 (2015).

    Article  CAS  PubMed  Google Scholar 

  248. Schneider, L. et al. Directional cell migration and chemotaxis in wound healing response to PDGF-AA are coordinated by the primary cilium in fibroblasts. Cell. Physiol. Biochem. 25, 279–292 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Schneider, L. et al. The Na+/H+ exchanger NHE1 is required for directional migration stimulated via PDGFR-α in the primary cilium. J. Cell Biol. 185, 163–176 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Clement, D. L. et al. PDGFRα signaling in the primary cilium regulates NHE1-dependent fibroblast migration via coordinated differential activity of MEK1/2–ERK1/2–p90RSK and AKT signaling pathways. J. Cell Sci. 126, 953–965 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Umberger, N. L. & Caspary, T. Ciliary transport regulates PDGF-AA/αα signaling via elevated mammalian target of rapamycin signaling and diminished PP2A activity. Mol. Biol. Cell 26, 350–358 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  252. Suizu, F. et al. Phosphorylation-dependent Akt–Inversin interaction at the basal body of primary cilia. EMBO J. 35, 1346–1363 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. O’Driscoll, M., Ruiz-Perez, V. L., Woods, C. G., Jeggo, P. A. & Goodship, J. A. A splicing mutation affecting expression of ataxia–telangiectasia and Rad3–related protein (ATR) results in Seckel syndrome. Nat. Genet. 33, 497 (2003).

    Article  PubMed  CAS  Google Scholar 

  254. Stiff, T., Casar Tena, T., O’Driscoll, M., Jeggo, P. A. & Philipp, M. ATR promotes cilia signalling: links to developmental impacts. Hum. Mol. Genet. 25, 1574–1587 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Vierkotten, J., Dildrop, R., Peters, T., Wang, B. & Rüther, U. Ftm is a novel basal body protein of cilia involved in Shh signalling. Development 134, 2569–2577 (2007).

    Article  CAS  PubMed  Google Scholar 

  256. Koefoed, K., Veland, I. R., Pedersen, L. B., Larsen, L. A. & Christensen, S. T. Cilia and coordination of signaling networks during heart development. Organogenesis 10, 108–125 (2014).

    Article  PubMed  Google Scholar 

  257. Mohapatra, B. et al. Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases. Biochim. Biophys. Acta 1833, 122–139 (2013).

    Article  CAS  PubMed  Google Scholar 

  258. Liyasova, M. S., Ma, K. & Lipkowitz, S. Molecular pathways: Cbl proteins in tumorigenesis and antitumor immunity — opportunities for cancer treatment. Clin. Cancer Res. 21, 1789–1794 (2015).

    Article  CAS  PubMed  Google Scholar 

  259. Schmid, F. M. et al. IFT20 modulates ciliary PDGFRalpha signaling by regulating the stability of Cbl E3 ubiquitin ligases. J. Cell Biol. 217, 151–161 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Szucs, Z. et al. Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications. Future Oncol. 13, 93–107 (2017).

    Article  CAS  PubMed  Google Scholar 

  261. Mohapatra, B. et al. An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. Development 144, 1072–1086 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Bielas, S. L. et al. Mutations in the inositol polyphosphate-5-phosphatase E gene link phosphatidyl inositol signaling to the ciliopathies. Nat. Genet. 41, 1032–1036 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Kisseleva, M. V., Cao, L. & Majerus, P. W. Phosphoinositide-specific inositol polyphosphate 5-phosphatase IV inhibits Akt/protein kinase B phosphorylation and leads to apoptotic cell death. J. Biol. Chem. 277, 6266–6272 (2002).

    Article  CAS  PubMed  Google Scholar 

  264. Jacoby, M. et al. INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat. Genet. 41, 1027 (2009).

    Article  CAS  PubMed  Google Scholar 

  265. Nickel, J., ten Dijke, P. & Mueller, T. D. TGF-β family co-receptor function and signaling. Acta Biochim. Biophys. Sin. 50, 12–36 (2018).

    Article  CAS  PubMed  Google Scholar 

  266. Heldin, C.-H. & Moustakas, A. Signaling receptors for TGF-β family members. Cold Spring Harb. Perspect. Biol. 8, a022053 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  267. Luo, K. Signaling cross talk between TGF-β/Smad and other signaling pathways. Cold Spring Harb. Perspect. Biol. 9, a022137 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  268. Bakkebø, M. et al. SARA is dispensable for functional TGF-β signaling. FEBS Lett. 586, 3367–3372 (2012).

    Article  PubMed  CAS  Google Scholar 

  269. Clement, C. A. et al. TGF-β signaling is associated with endocytosis at the pocket region of the primary cilium. Cell Rep. 3, 1806–1814 (2013).

    Article  CAS  PubMed  Google Scholar 

  270. Xie, Y.-F. et al. Pulsed electromagnetic fields stimulate osteogenic differentiation and maturation of osteoblasts by upregulating the expression of BMPRII localized at the base of primary cilium. Bone 93, 22–32 (2016).

    Article  CAS  PubMed  Google Scholar 

  271. Labour, M.-N., Riffault, M., Christensen, S. T. & Hoey, D. A. TGFβ1 – induced recruitment of human bone mesenchymal stem cells is mediated by the primary cilium in a SMAD3-dependent manner. Sci. Rep. 6, 35542 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Zhang, J. et al. Topography of calcium phosphate ceramics regulates primary cilia length and TGF receptor recruitment associated with osteogenesis. Acta Biomater. 57, 487–497 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Gencer, S. et al. TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis. Sci. Signal. 10, eaam7464 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  274. Koefoed, K. et al. The E3 ubiquitin ligase SMURF1 regulates cell-fate specification and outflow tract septation during mammalian heart development. Sci. Rep. 8, 9542 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Arrighi, N. et al. The primary cilium is necessary for the differentiation and the maintenance of human adipose progenitors into myofibroblasts. Sci. Rep. 7, 15248 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Goetz & Jacky, G. et al. Endothelial cilia mediate low flow sensing during zebrafish vascular development. Cell Rep. 6, 799–808 (2014).

    Article  CAS  PubMed  Google Scholar 

  277. Kallakuri, S. et al. Endothelial cilia are essential for developmental vascular integrity in zebrafish. J. Am. Soc. Nephrol. 26, 864–875 (2015).

    Article  CAS  PubMed  Google Scholar 

  278. Hierck, B. P. et al. Primary cilia sensitize endothelial cells for fluid shear stress. Dev. Dyn. 237, 725–735 (2008).

    Article  CAS  PubMed  Google Scholar 

  279. Egorova, A. D. et al. Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition. Circ. Res. 108, 1093–1101 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Vion, A.-C. et al. Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regression. J. Cell Biol. 217, 1651–1665 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Kawasaki, M. et al. TGF-β suppresses Ift88 expression in chondrocytic ATDC5 cells. J. Cell. Physiol. 230, 2788–2795 (2015).

    Article  CAS  PubMed  Google Scholar 

  282. Ehnert, S. et al. TGF-β1 impairs mechanosensation of human osteoblasts via HDAC6-mediated shortening and distortion of primary cilia. J. Mol. Med. 95, 653–663 (2017).

    Article  CAS  PubMed  Google Scholar 

  283. Han, S. J. et al. Deficiency of primary cilia in kidney epithelial cells induces epithelial to mesenchymal transition. Biochem. Biophys. Res. Commun. 496, 450–454 (2018).

    Article  CAS  PubMed  Google Scholar 

  284. Westlake, C. J. et al. Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome. Proc. Natl Acad. Sci. USA 108, 2759–2764 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Mitchell, H., Choudhury, A., Pagano, R. E. & Leof, E. B. Ligand-dependent and -independent transforming growth factor-β receptor recycling regulated by clathrin-mediated endocytosis and Rab11. Mol. Biol. Cell 15, 4166–4178 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Monnich, M. et al. CEP128 localizes to the subdistal appendages of the mother centriole and regulates TGF-β/BMP signaling at the primary cilium. Cell Rep. 22, 2584–2592 (2018).

    Article  CAS  PubMed  Google Scholar 

  287. Miyazawa, K. & Miyazono, K. Regulation of TGF-β family signaling by inhibitory smads. Cold Spring Harb. Perspect. Biol. 9, a022095 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  288. Rosengren, T., Larsen, L. J., Pedersen, L. B., Christensen, S. T. & Møller, L. B. TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms. Cell. Mol. Life Sci. 75, 2663–2680 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Pedersen, L. B., Mogensen, J. B. & Christensen, S. T. Endocytic control of cellular signaling at the primary cilium. Trends Biochem. Sci. 41, 784–797 (2016).

    Article  CAS  PubMed  Google Scholar 

  290. Wheway, G., Nazlamova, L. & Hancock, J. T. Signaling through the primary cilium. Front. Cell Dev. Biol. 6, 8 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  291. Seeger-Nukpezah, T. & Golemis, E. A. The extracellular matrix and ciliary signaling. Curr. Opin. Cell Biol. 24, 652–661 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Wood, C. R. & Rosenbaum, J. L. Ciliary ectosomes: transmissions from the cell’s antenna. Trends Cell Biol. 25, 276–285 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Pampliega, O. et al. Functional interaction between autophagy and ciliogenesis. Nature 502, 194–200 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Lee, K. H. et al. Identification of a novel Wnt5a-CK1varepsilon-Dvl2-Plk1-mediated primary cilia disassembly pathway. EMBO J. 31, 3104–3117 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Yao, G. et al. Disruption of polycystin-L causes hippocampal and thalamocortical hyperexcitability. Hum. Mol. Genet. 25, 448–458 (2016).

    Article  CAS  PubMed  Google Scholar 

  296. Abdul-Majeed, S. & Nauli, S. M. Dopamine receptor type 5 in the primary cilia has dual chemo- and mechano-sensory roles. Hypertension 58, 325–331 (2011).

    Article  CAS  PubMed  Google Scholar 

  297. Koemeter-Cox, A. I. et al. Primary cilia enhance kisspeptin receptor signaling on gonadotropin-releasing hormone neurons. Proc. Natl Acad. Sci. USA 111, 10335–10340 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Berbari, N. F., Johnson, A. D., Lewis, J. S., Askwith, C. C. & Mykytyn, K. Identification of ciliary localization sequences within the third intracellular loop of G protein-coupled receptors. Mol. Biol. Cell 19, 1540–1547 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Jiang, Y., Li, Y. R., Tian, H., Ma, M. & Matsunami, H. Muscarinic acetylcholine receptor M3 modulates odorant receptor activity via inhibition of β-arrestin-2 recruitment. Nat. Commun. 6, 6448 (2015).

    Article  CAS  PubMed  Google Scholar 

  300. Zheng, L. et al. Ciliary parathyroid hormone signaling activates transforming growth factor-beta to maintain intervertebral disc homeostasis during aging. Bone Res. 6, 21 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  301. Omori, Y. et al. Identification of G protein-coupled receptors (GPCRs) in primary cilia and their possible involvement in body weight control. PLOS ONE 10, e0128422 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  302. Jin, D. et al. Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport. Nat. Cell Biol. 16, 841–851 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. Brailov, I. et al. Localization of 5-HT6 receptors at the plasma membrane of neuronal cilia in the rat brain. Brain Res. 872, 271–275 (2000).

    Article  CAS  PubMed  Google Scholar 

  304. Handel, M. et al. Selective targeting of somatostatin receptor 3 to neuronal cilia. Neuroscience 89, 909–926 (1999).

    Article  CAS  PubMed  Google Scholar 

  305. Szumska, J. et al. Trace amine-associated receptor 1 localization at the apical plasma membrane domain of fisher rat thyroid epithelial cells is confined to cilia. Eur. Thyroid J. 4, 30–41 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors’ work presented in this Review was supported by Independent Research Fund Denmark (6108-00457B and 8020-00162B to S.T.C. and L.B.P.), the Danish Cancer Society (R146-A9590-16-S2 to L.B.P. and Z.A.), Brødrene Hartmanns Fond (A31662 to L.B.P.), research project grant R21 MH107021 from the US National Institutes of Health (NIH) National Institute of Mental Health (to K.M.), a grant from Alex’s Lemonade Foundation (to S.M.), a Welch Foundation Grant (I-1906 to S.M.) and an R01 grant from NIH (1R01GM113023 to S.M.). The authors are grateful to S. K. Morthorst, University of Copenhagen, for help with formatting the references and the three reviewers for their insightful and constructive comments. The authors apologize to those authors whose work has not been cited because of space limitations.

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Nature Reviews Nephrology thanks M. Nachury, P. Tran and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Anvarian, Z., Mykytyn, K., Mukhopadhyay, S. et al. Cellular signalling by primary cilia in development, organ function and disease. Nat Rev Nephrol 15, 199–219 (2019). https://doi.org/10.1038/s41581-019-0116-9

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