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Primary cilia as dynamic and diverse signalling hubs in development and disease

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From Nature Reviews Genetics

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Abstract

Primary cilia, antenna-like sensory organelles protruding from the surface of most vertebrate cell types, are essential for regulating signalling pathways during development and adult homeostasis. Mutations in genes affecting cilia cause an overlapping spectrum of >30 human diseases and syndromes, the ciliopathies. Given the immense structural and functional diversity of the mammalian cilia repertoire, there is a growing disconnect between patient genotype and associated phenotypes, with variable severity and expressivity characteristic of the ciliopathies as a group. Recent technological developments are rapidly advancing our understanding of the complex mechanisms that control biogenesis and function of primary cilia across a range of cell types and are starting to tackle this diversity. Here, we examine the structural and functional diversity of primary cilia, their dynamic regulation in different cellular and developmental contexts and their disruption in disease.

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Fig. 1: Architecture of primary cilia and main ciliary subcompartments.
Fig. 2: Overview of signalling pathways coordinated by primary cilia.
Fig. 3: Ciliary dynamics.
Fig. 4: Challenge of ciliopathies — biology across scales.

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References

  1. Niederlova, V., Modrak, M., Tsyklauri, O., Huranova, M. & Stepanek, O. Meta-analysis of genotype-phenotype associations in Bardet-Biedl syndrome uncovers differences among causative genes. Hum. Mutat. 40, 2068–2087 (2019).

    Article  CAS  PubMed  Google Scholar 

  2. 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 

  3. Wheway, G., Mitchison, H. M. & Genomics England Research, C. Opportunities and challenges for molecular understanding of ciliopathies — the 100,000 Genomes Project. Front. Genet. 10, 127 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chandra, B., Tung, M. L., Hsu, Y., Scheetz, T. & Sheffield, V. C. Retinal ciliopathies through the lens of Bardet-Biedl syndrome: past, present and future. Prog. Retin. Eye Res. 89, 101035 (2022).

    Article  CAS  PubMed  Google Scholar 

  5. Van De Weghe, J. C., Gomez, A. & Doherty, D. The Joubert-Meckel-Nephronophthisis spectrum of ciliopathies. Annu. Rev. Genomics Hum. Genet. 23, 301–329 (2022).

    Article  PubMed  Google Scholar 

  6. Wallmeier, J. et al. Motile ciliopathies. Nat. Rev. Dis. Prim. 6, 77 (2020).

    Article  PubMed  Google Scholar 

  7. Lovera, M. & Luders, J. The ciliary impact of nonciliary gene mutations. Trends Cell Biol. 31, 876–887 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Pigino, G. Intraflagellar transport. Curr. Biol. 31, R530–R536 (2021).

    Article  CAS  PubMed  Google Scholar 

  9. Legendre, M., Zaragosi, L. E. & Mitchison, H. M. Motile cilia and airway disease. Semin. Cell Dev. Biol. 110, 19–33 (2021).

    Article  CAS  PubMed  Google Scholar 

  10. Kumar, D. et al. A ciliopathy complex builds distal appendages to initiate ciliogenesis. J. Cell Biol. https://doi.org/10.1083/jcb.202011133 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Diener, D. R., Lupetti, P. & Rosenbaum, J. L. Proteomic analysis of isolated ciliary transition zones reveals the presence of ESCRT proteins. Curr. Biol. 25, 379–384 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sang, L. et al. Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145, 513–528 (2011). Using high-confidence proteomics, this study identifies 850 interactors of nine NPHP/JBTS/MKS proteins and describes ATXN10 and TCTN2 as new NPHP/JBTS genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chih, B. et al. A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat. Cell Biol. 14, 61–72 (2011).

    Article  PubMed  Google Scholar 

  14. Garcia-Gonzalo, F. R. & Reiter, J. F. Open sesame: how transition fibers and the transition zone control ciliary composition. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a028134 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Trepout, S., Tassin, A. M., Marco, S. & Bastin, P. STEM tomography analysis of the trypanosome transition zone. J. Struct. Biol. 202, 51–60 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Greenan, G. A., Vale, R. D. & Agard, D. A. Electron cryotomography of intact motile cilia defines the basal body to axoneme transition. J. Cell Biol. https://doi.org/10.1083/jcb.201907060 (2020).

    Article  PubMed  Google Scholar 

  17. Yang, T. T. et al. Superresolution pattern recognition reveals the architectural map of the ciliary transition zone. Sci. Rep. 5, 14096 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Jana, S. C. et al. Differential regulation of transition zone and centriole proteins contributes to ciliary base diversity. Nat. Cell Biol. 20, 928–941 (2018).

    Article  CAS  PubMed  Google Scholar 

  19. Hazime, K. S. et al. STORM imaging reveals the spatial arrangement of transition zone components and IFT particles at the ciliary base in Tetrahymena. Sci. Rep. 11, 7899 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Conduit, S. E. & Vanhaesebroeck, B. Phosphoinositide lipids in primary cilia biology. Biochem. J. 477, 3541–3565 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Fisch, C. & Dupuis-Williams, P. Ultrastructure of cilia and flagella — back to the future! Biol. Cell 103, 249–270 (2011).

    Article  PubMed  Google Scholar 

  22. Gilliam, J. C. et al. Three-dimensional architecture of the rod sensory cilium and its disruption in retinal neurodegeneration. Cell 151, 1029–1041 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wiegering, A. et al. Cell type-specific regulation of ciliary transition zone assembly in vertebrates. EMBO J. https://doi.org/10.15252/embj.201797791 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Garcia-Gonzalo, F. R. et al. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat. Genet. 43, 776–784 (2011). Together with Sang et al. (2011) and Chih et al. (2011), this study identifies a complex of nine proteins (the MKS complex) at the ciliary transition zone that regulates ciliary assembly and composition, several of which are mutated in MKS or JBTS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nachury, M. V. & Mick, D. U. Establishing and regulating the composition of cilia for signal transduction. Nat. Rev. Mol. Cell Biol. 20, 389–405 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

  27. 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 

  28. 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 

  29. Palicharla, V. R. et al. Interactions between TULP3 tubby domain and ARL13B amphipathic helix promote lipidated protein transport to cilia. Mol. Biol. Cell https://doi.org/10.1091/mbc.E22-10-0473 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hesketh, S. J., Mukhopadhyay, A. G., Nakamura, D., Toropova, K. & Roberts, A. J. IFT-A structure reveals carriages for membrane protein transport into cilia. Cell 185, 4971–4985.e16 (2022).

    Article  CAS  PubMed  Google Scholar 

  31. 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). This first study to purify and characterize IFT-A and IFT-B polypeptides using Chlamydomonas flagella reveals that Chlamydomonas IFT polypeptides are homologous to proteins required for biogenesis of neuronal sensory cilia in C. elegans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Matsuura, K., Lefebvre, P. A., Kamiya, R. & Hirono, M. Kinesin-II is not essential for mitosis and cell growth in Chlamydomonas. Cell Motil. Cytoskeleton 52, 195–201 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. van den Hoek, H. et al. In situ architecture of the ciliary base reveals the stepwise assembly of intraflagellar transport trains. Science 377, 543–548 (2022).

    Article  PubMed  Google Scholar 

  34. Lechtreck, K. Cargo adapters expand the transport range of intraflagellar transport. J. Cell Sci. https://doi.org/10.1242/jcs.260408 (2022).

    Article  PubMed  Google Scholar 

  35. Ocbina, P. J. & Anderson, K. V. Intraflagellar transport, cilia, and mammalian Hedgehog signaling: analysis in mouse embryonic fibroblasts. Dev. Dyn. 237, 2030–2038 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 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 

  37. Goggolidou, P. et al. ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis. Development 141, 3966–3977 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. De-Castro, A. R. G. et al. WDR60-mediated dynein-2 loading into cilia powers retrograde IFT and transition zone crossing. J. Cell Biol. https://doi.org/10.1083/jcb.202010178 (2022).

    Article  PubMed  Google Scholar 

  39. Jensen, V. L. et al. Role for intraflagellar transport in building a functional transition zone. EMBO Rep. https://doi.org/10.15252/embr.201845862 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Scheidel, N. & Blacque, O. E. Intraflagellar transport complex A genes differentially regulate cilium formation and transition zone gating. Curr. Biol. 28, 3279–3287.e2 (2018).

    Article  CAS  PubMed  Google Scholar 

  41. den Hollander, A. I., Roepman, R., Koenekoop, R. K. & Cremers, F. P. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog. Retin. Eye Res. 27, 391–419 (2008).

    Article  Google Scholar 

  42. Xu, M. et al. Mutations in human IFT140 cause non-syndromic retinal degeneration. Hum. Genet. 134, 1069–1078 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Parfitt, D. A. et al. Identification and correction of mechanisms underlying inherited blindness in human iPSC-derived optic cups. Cell Stem Cell 18, 769–781 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Russell, S. R. et al. Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial. Nat. Med. 28, 1014–1021 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Editas Medicine, Inc. Single ascending dose study in participants with LCA10. U. S. National Library of Medicine ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03872479#moreinfo (2022).

  46. Sun, S., Fisher, R. L., Bowser, S. S., Pentecost, B. T. & Sui, H. Three-dimensional architecture of epithelial primary cilia. Proc. Natl Acad. Sci. USA 116, 9370–9379 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kiesel, P. et al. The molecular structure of mammalian primary cilia revealed by cryo-electron tomography. Nat. Struct. Mol. Biol. 27, 1115–1124 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu, Z. et al. Super-resolution microscopy and FIB-SEM imaging reveal parental centriole-derived, hybrid cilium in mammalian multiciliated cells. Dev. Cell 55, 224–236.e6 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Xu, C. S. et al. An open-access volume electron microscopy atlas of whole cells and tissues. Nature 599, 147–151 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Barnes, C. L., Malhotra, H. & Calvert, P. D. Compartmentalization of photoreceptor sensory cilia. Front. Cell Dev. Biol. 9, 636737 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Silverman, M. A. & Leroux, M. R. Intraflagellar transport and the generation of dynamic, structurally and functionally diverse cilia. Trends Cell Biol. 19, 306–316 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Gluenz, E. et al. Beyond 9 + 0: noncanonical axoneme structures characterize sensory cilia from protists to humans. FASEB J. 24, 3117–3121 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Steib, E. et al. TissUExM enables quantitative ultrastructural analysis in whole vertebrate embryos by expansion microscopy. Cell Rep. Methods 2, 100311 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Flock, A. & Duvall, A. J. III The ultrastructure of the kinocilium of the sensory cells in the inner ear and lateral line organs. J. Cell Biol. 25, 1–8 (1965).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  56. Jafek, B. W. Ultrastructure of human nasal mucosa. Laryngoscope 93, 1576–1599 (1983).

    Article  CAS  PubMed  Google Scholar 

  57. Jenkins, P. M., McEwen, D. P. & Martens, J. R. Olfactory cilia: linking sensory cilia function and human disease. Chem. Senses 34, 451–464 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nonami, Y., Narita, K., Nakamura, H., Inoue, T. & Takeda, S. Developmental changes in ciliary motility on choroid plexus epithelial cells during the perinatal period. Cytoskeleton 70, 797–803 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Cho, J. H. et al. Islet primary cilia motility controls insulin secretion. Sci. Adv. 8, eabq8486 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mallet, A. & Bastin, P. Restriction of intraflagellar transport to some microtubule doublets: an opportunity for cilia diversification? Bioessays 44, e2200031 (2022).

    Article  PubMed  Google Scholar 

  61. Evans, J. E. et al. Functional modulation of IFT kinesins extends the sensory repertoire of ciliated neurons in Caenorhabditis elegans. J. Cell Biol. 172, 663–669 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pooranachandran, N. & Malicki, J. J. Unexpected roles for ciliary kinesins and intraflagellar transport proteins. Genetics 203, 771–785 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lewis, T. R. et al. Cos2/Kif7 and Osm-3/Kif17 regulate onset of outer segment development in zebrafish photoreceptors through distinct mechanisms. Dev. Biol. 425, 176–190 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Stepanek, L. & Pigino, G. Microtubule doublets are double-track railways for intraflagellar transport trains. Science 352, 721–724 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Bertiaux, E. et al. Bidirectional intraflagellar transport is restricted to two sets of microtubule doublets in the trypanosome flagellum. J. Cell Biol. 217, 4284–4297 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Silva, M. et al. Cell-specific alpha-tubulin isotype regulates ciliary microtubule ultrastructure, intraflagellar transport, and extracellular vesicle biology. Curr. Biol. 27, 968–980 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mechaussier, S. et al. TUBB4B variants specifically impact ciliary function, causing a ciliopathic spectrum. Preprint at medRxiv https://doi.org/10.1101/2022.10.19.22280748 (2022).

    Article  Google Scholar 

  68. Yu, I., Garnham, C. P. & Roll-Mecak, A. Writing and reading the tubulin code. J. Biol. Chem. 290, 17163–17172 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Magiera, M. M., Singh, P., Gadadhar, S. & Janke, C. Tubulin posttranslational modifications and emerging links to human disease. Cell 173, 1323–1327 (2018).

    Article  CAS  PubMed  Google Scholar 

  70. Gadadhar, S. et al. Tubulin glycylation controls axonemal dynein activity, flagellar beat, and male fertility. Science https://doi.org/10.1126/science.abd4914 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Bosch Grau, M. et al. Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration. J. Cell Sci. 130, 938–949 (2017).

    Article  PubMed  Google Scholar 

  72. O’Hagan, R. et al. Glutamylation regulates transport, specializes function, and sculpts the structure of cilia. Curr. Biol. 27, 3430–3441.e6 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Power, K. M. et al. Mutation of NEKL-4/NEK10 and TTLL genes suppress neuronal ciliary degeneration caused by loss of CCPP-1 deglutamylase function. PLoS Genet. 16, e1009052 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mukhopadhyay, S. et al. Distinct IFT mechanisms contribute to the generation of ciliary structural diversity in C. elegans. EMBO J. 26, 2966–2980 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Garcia, G. III, Raleigh, D. R. & Reiter, J. F. How the ciliary membrane is organized inside-out to communicate outside-in. Curr. Biol. 28, R421–R434 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mukhopadhyay, S., Lu, Y., Shaham, S. & Sengupta, P. Sensory signaling-dependent remodeling of olfactory cilia architecture in C. elegans. Dev. Cell 14, 762–774 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Besschetnova, T. Y. et al. Identification of signaling pathways regulating primary cilium length and flow-mediated adaptation. Curr. Biol. 20, 182–187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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). By using C. elegans as a model, this study is the first to report cilia-associated functions for polycystins.

    Article  CAS  PubMed  Google Scholar 

  79. 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 

  80. 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). Together with Yoder et al. (2002), this study is one of the first to show localization of polycystins to primary cilia in mammalian kidney epithelial cells.

    Article  CAS  PubMed  Google Scholar 

  81. Ma, M., Gallagher, A. R. & Somlo, S. Ciliary mechanisms of cyst formation in polycystic kidney disease. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a028209 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Corbit, K. C. et al. Vertebrate smoothened functions at the primary cilium. Nature 437, 1018 (2005). This is the first study showing that Smoothened localizes to and functions at the primary cilium to control Hedgehog signalling in vertebrates.

    Article  CAS  PubMed  Google Scholar 

  83. Rohatgi, R., Milenkovic, L. & Scott, M. P. Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372–376 (2007). This study is the first to show that PTCH1 localizes to the primary cilium to prevent entry of SMO to the cilium; when SHH binds to PTCH1, the receptor leaves the cilium, allowing ciliary accumulation of SMO to activate signalling.

    Article  CAS  PubMed  Google Scholar 

  84. Bangs, F. & Anderson, K. V. Primary cilia and mammalian hedgehog signaling. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a028175 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Katoh, T. A. et al. Immotile cilia mechanically sense the direction of fluid flow for left-right determination. Science 379, 66–71 (2023).

    Article  CAS  PubMed  Google Scholar 

  86. Hilgendorf, K. I., Johnson, C. T. & Jackson, P. K. The primary cilium as a cellular receiver: organizing ciliary GPCR signaling. Curr. Opin. Cell Biol. 39, 84–92 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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 β (TGF-β) signaling. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a028167 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Mick, D. U. et al. Proteomics of primary cilia by proximity labeling. Dev. Cell 35, 497–512 (2015). This study is the first to use cilium-targeted proximity-labelling proteomics to identify the proteome of primary cilia of cultured mammalian cells and reveal how it is altered in Ift27/Bbs19 mutant cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Datta, P. et al. Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome. Proc. Natl Acad. Sci. USA 112, E4400–E4409 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kohli, P. et al. The ciliary membrane-associated proteome reveals actin-binding proteins as key components of cilia. EMBO Rep. 18, 1521–1535 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. May, E. A. et al. Time-resolved proteomics profiling of the ciliary Hedgehog response. J. Cell Biol. https://doi.org/10.1083/jcb.202007207 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Liu, X. et al. Cilium proteomics reveals Numb as a positive regulator of the Hedgehog signaling pathway. Preprint at bioRxiv https://doi.org/10.1101/2022.10.10.511655 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Masek, M. et al. Loss of the Bardet-Biedl protein Bbs1 alters photoreceptor outer segment protein and lipid composition. Nat. Commun. 13, 1282 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Quidwai, T. et al. A WDR35-dependent coat protein complex transports ciliary membrane cargo vesicles to cilia. eLife https://doi.org/10.7554/eLife.69786 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wu, D. et al. Ciliogenesis requires sphingolipid-dependent membrane and axoneme interaction. Proc. Natl Acad. Sci. USA 119, e2201096119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Meleppattu, S., Zhou, H., Dai, J., Gui, M. & Brown, A. Mechanism of IFT-A polymerization into trains for ciliary transport. Cell 185, 4986–4998 e4912 (2022).

    Article  CAS  PubMed  Google Scholar 

  97. 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. https://doi.org/10.1083/jcb.201709041 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Caspary, T., Larkins, C. E. & Anderson, K. V. The graded response to Sonic hedgehog depends on cilia architecture. Dev. Cell 12, 767–778 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Cantagrel, V. et al. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am. J. Hum. Genet. 83, 170–179 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cevik, S. et al. Joubert syndrome Arl13b functions at ciliary membranes and stabilizes protein transport in Caenorhabditis elegans. J. Cell Biol. 188, 953–969 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Nozaki, S. et al. Regulation of ciliary retrograde protein trafficking by the Joubert syndrome proteins ARL13B and INPP5E. J. Cell Sci. 130, 563–576 (2017).

    CAS  PubMed  Google Scholar 

  102. Han, S. et al. TULP3 is required for localization of membrane-associated proteins ARL13B and INPP5E to primary cilia. Biochem. Biophys. Res. Commun. 509, 227–234 (2019).

    Article  CAS  PubMed  Google Scholar 

  103. Legue, E. & Liem, K. F. Jr Tulp3 is a ciliary trafficking gene that regulates polycystic kidney disease. Curr. Biol. 29, 803–812 e805 (2019).

    Article  CAS  PubMed  Google Scholar 

  104. Jensen, V. L. & Leroux, M. R. Gates for soluble and membrane proteins, and two trafficking systems (IFT and LIFT), establish a dynamic ciliary signaling compartment. Curr. Opin. Cell Biol. 47, 83–91 (2017).

    Article  CAS  PubMed  Google Scholar 

  105. Kanie, T. et al. The CEP19-RABL2 GTPase complex binds IFT-B to initiate intraflagellar transport at the ciliary base. Dev. Cell 42, 22–36.e12 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Boegholm, N. et al. The IFT81-IFT74 complex enhances GTP hydrolysis to inactivate RabL2 during early steps of intraflagellar transport. Preprint at bioRxiv https://doi.org/10.1101/2022.05.31.494111 (2022).

    Article  Google Scholar 

  107. Duan, S. et al. Rabl2 GTP hydrolysis licenses BBSome-mediated export to fine-tune ciliary signaling. EMBO J. 40, e105499 (2021).

    Article  CAS  PubMed  Google Scholar 

  108. 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). This study first identified the BBSome using cultured mammalian cells as a model.

    Article  CAS  PubMed  Google Scholar 

  109. Desai, P. B., Stuck, M. W., Lv, B. & Pazour, G. J. Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling. J. Cell Biol. https://doi.org/10.1083/jcb.201912104 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Shinde, S. R. et al. The ancestral ESCRT protein TOM1L2 selects ubiquitinated cargoes for retrieval from cilia. Preprint at bioRxiv https://doi.org/10.1101/2022.09.23.509287 (2022).

  111. 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 

  112. Jacoby, M. et al. INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat. Genet. 41, 1027 (2009). Together with Bielas et al. (2009), this study is one of the first to report that mutations in the INPP5E gene are causative of human ciliopathies.

    Article  CAS  PubMed  Google Scholar 

  113. 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 

  114. Garcia-Gonzalo, F. R. et al. Phosphoinositides regulate ciliary protein trafficking to modulate hedgehog signaling. Dev. Cell 34, 400–409 (2015). Together with Chavez et al. (2015), this study shows that INPP5E is required for enrichment of PtdIns4P in the ciliary membrane, which in turn is needed for appropriate regulation of Hedgehog signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Dyson, J. M. et al. INPP5E regulates phosphoinositide-dependent cilia transition zone function. J. Cell Biol. 216, 247–263 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tripathi, P. et al. Palmitoylation of acetylated tubulin and association with ceramide-rich platforms is critical for ciliogenesis. J. Lipid Res. 62, 100021 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nguyen, T. D., Truong, M. E. & Reiter, J. F. The intimate connection between lipids and hedgehog signaling. Front. Cell Dev. Biol. 10, 876815 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Shakya, S. & Westlake, C. J. Recent advances in understanding assembly of the primary cilium membrane. Fac. Rev. 10, 16 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sedmak, T. & Wolfrum, U. Intraflagellar transport proteins in ciliogenesis of photoreceptor cells. Biol. Cell 103, 449–466 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Labat-de-Hoz, L. et al. A model for primary cilium biogenesis by polarized epithelial cells: role of the midbody remnant and associated specialized membranes. Front. Cell Dev. Biol. 8, 622918 (2020).

    Article  PubMed  Google Scholar 

  121. Stuck, M. W., Chong, W. M., Liao, J. C. & Pazour, G. J. Rab34 is necessary for early stages of intracellular ciliogenesis. Curr. Biol. 31, 2887–2894.e4 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ganga, A. K. et al. Rab34 GTPase mediates ciliary membrane formation in the intracellular ciliogenesis pathway. Curr. Biol. 31, 2895–2905.e7 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Benmerah, A. The ciliary pocket. Curr. Opin. Cell Biol. 25, 78–84 (2013).

    Article  CAS  PubMed  Google Scholar 

  124. 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 

  125. Ojeda Naharros, I. & Nachury, M. V. Shedding of ciliary vesicles at a glance. J. Cell Sci. https://doi.org/10.1242/jcs.246553 (2022).

    Article  PubMed  Google Scholar 

  126. Anvarian, Z., Mykytyn, K., Mukhopadhyay, S., Pedersen, L. B. & Christensen, S. T. Cellular signalling by primary cilia in development, organ function and disease. Nat. Rev. Nephrol. 15, 199–219 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  127. 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 

  128. Hilgendorf, K. I. Primary cilia are critical regulators of white adipose tissue expansion. Front. Physiol. 12, 769367 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wachten, D. & Mick, D. U. Signal transduction in primary cilia — analyzing and manipulating GPCR and second messenger signaling. Pharmacol. Ther. 224, 107836 (2021).

    Article  CAS  PubMed  Google Scholar 

  130. Happ, J. T. et al. A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction. Nat. Struct. Mol. Biol. 29, 990–999 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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 

  132. May, E. A., Sroka, T. J. & Mick, D. U. Phosphorylation and ubiquitylation regulate protein trafficking, signaling, and the biogenesis of primary cilia. Front. Cell Dev. Biol. 9, 664279 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Shinde, S. R., Nager, A. R. & Nachury, M. V. Ubiquitin chains earmark GPCRs for BBSome-mediated removal from cilia. J. Cell Biol. https://doi.org/10.1083/jcb.202003020 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Lv, B., Stuck, M. W., Desai, P. B., Cabrera, O. A. & Pazour, G. J. E3 ubiquitin ligase Wwp1 regulates ciliary dynamics of the Hedgehog receptor Smoothened. J. Cell Biol. https://doi.org/10.1083/jcb.202010177 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  135. 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 

  136. Chiuso, F. et al. Ubiquitylation of BBSome is required for ciliary assembly and signaling. EMBO Rep. https://doi.org/10.15252/embr.202255571 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Yue, S. et al. Requirement of Smurf-mediated endocytosis of Patched1 in Sonic hedgehog signal reception. eLife https://doi.org/10.7554/eLife.02555 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Hantel, F. et al. Cilia-localized GID/CTLH ubiquitin ligase complex regulates protein homeostasis of Sonic hedgehog signaling components. J. Cell Sci. https://doi.org/10.1242/jcs.259209 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Schneider, L. et al. PDGFRαα signaling is regulated through the primary cilium in fibroblasts. Curr. Biol. 15, 1861–1866 (2005). This is the first study to show that PDGFRα localizes to and functions at the primary cilium in cultured vertebrate cells (mouse fibroblasts).

    Article  CAS  PubMed  Google Scholar 

  140. 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 

  141. 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). This is the first study showing that TGFβ signalling is regulated by receptors in the primary cilium and controlled at the level of clathrin-mediated endocytosis at the ciliary pocket in vertebrates.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 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 

  144. Hossain, D. & Tsang, W. Y. The role of ubiquitination in the regulation of primary cilia assembly and disassembly. Semin. Cell Dev. Biol. 93, 145–152 (2019).

    Article  CAS  PubMed  Google Scholar 

  145. Senatore, E. et al. Pathophysiology of primary cilia: signaling and proteostasis regulation. Front. Cell Dev. Biol. 10, 833086 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Aslanyan, M. G. et al. A targeted multi-proteomics approach generates a blueprint of the ciliary ubiquitinome. Front. Cell Dev. Biol. https://doi.org/10.3389/fcell.2023.1113656 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Sanchez, G. M. et al. The beta-cell primary cilium is an autonomous Ca2+ compartment for paracrine GABA signaling. J. Cell Biol. https://doi.org/10.1083/jcb.202108101 (2023). This study shows that GABAB1 receptors localize to primary cilia of β-cells in pancreatic islets of Langerhans to induce selective Ca2+ influx in the cilium via voltage-dependent Ca2+ channel activation, and that GABA action depends on restricted Ca2+ diffusion between the cilium and cytosol.

    Article  PubMed  Google Scholar 

  148. Nauli, S. M., Pala, R. & Kleene, S. J. Calcium channels in primary cilia. Curr. Opin. Nephrol. Hypertens. 25, 452–458 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Saternos, H., Ley, S. & AbouAlaiwi, W. Primary cilia and calcium signaling interactions. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21197109 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Spasic, M. & Jacobs, C. R. Primary cilia: cell and molecular mechanosensors directing whole tissue function. Semin. Cell Dev. Biol. 71, 42–52 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Djenoune, L. et al. Cilia function as calcium-mediated mechanosensors that instruct left-right asymmetry. Science 379, 71–78 (2023). Together with Katoh et al. (2023), this study provides evidence that primary cilia of the left–right organizer are mechanosensors that translate extracellular fluid flow into Ca2+ signals to induce embryonic left–right asymmetry.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Tanaka, Y., Morozumi, A. & Hirokawa, N. Leftward transfer of a chemosensory polycystin initiates left-dominant calcium signaling for lateralized embryonic development. Preprint at bioRxiv https://doi.org/10.1101/2023.01.12.523739 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Djenoune, L., Berg, K., Brueckner, M. & Yuan, S. A change of heart: new roles for cilia in cardiac development and disease. Nat. Rev. Cardiol. 19, 211–227 (2022).

    Article  PubMed  Google Scholar 

  154. Okada, Y. et al. Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol. Cell 4, 459–468 (1999). This study shows that abnormal nodal flow at the left–right organizer leads to laterality defects in mutant mouse embryos.

    Article  CAS  PubMed  Google Scholar 

  155. Nonaka, S., Shiratori, H., Saijoh, Y. & Hamada, H. Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418, 96–99 (2002). This study uses artificial fluid flow at the node to control left–right patterning in mouse embryos, providing evidence for the role of mechanical fluid flow in embryonic symmetry breaking.

    Article  CAS  PubMed  Google Scholar 

  156. Little, R. B. & Norris, D. P. Right, left and cilia: how asymmetry is established. Semin. Cell Dev. Biol. 110, 11–18 (2021).

    Article  CAS  PubMed  Google Scholar 

  157. Brueckner, M. Heterotaxia, congenital heart disease, and primary ciliary dyskinesia. Circulation 115, 2793–2795 (2007).

    Article  PubMed  Google Scholar 

  158. Klena, N. T., Gibbs, B. C. & Lo, C. W. Cilia and ciliopathies in congenital heart disease. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a028266 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  159. 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 

  160. Wang, L. & Dynlacht, B. D. The regulation of cilium assembly and disassembly in development and disease. Development https://doi.org/10.1242/dev.151407 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Kasahara, K. & Inagaki, M. Primary ciliary signaling: links with the cell cycle. Trends Cell Biol. 31, 954–964 (2021).

    Article  CAS  PubMed  Google Scholar 

  162. Walia, V. et al. Akt Regulates a Rab11-effector switch required for ciliogenesis. Dev. Cell 50, 229–246.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Hu, H.-B. et al. LPA signaling acts as a cell-extrinsic mechanism to initiate cilia disassembly and promote neurogenesis. Nat. Commun. 12, 662 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 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 

  165. Zhang, Y. et al. Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol. Cell Biol. 28, 1688–1701 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Simon, D. et al. A mutation in the 3′-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia. Hum. Mol. Genet. 19, 2015–2027 (2010).

    Article  CAS  PubMed  Google Scholar 

  167. 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 

  168. Zhang, W. et al. Modeling microcephaly with cerebral organoids reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly in neural progenitors. Nat. Commun. 10, 2612 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Farooq, M. et al. RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis. Nat. Commun. 11, 5816 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Mirvis, M., Siemers, K. A., Nelson, W. J. & Stearns, T. P. Primary cilium loss in mammalian cells occurs predominantly by whole-cilium shedding. PLoS Biol. 17, e3000381 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Anderson, C. T. & Stearns, T. Centriole age underlies asynchronous primary cilium growth in mammalian cells. Curr. Biol. 19, 1498–1502 (2009). This paper shows that, following cell division, the daughter cell that inherits the older mother centriole ciliates and becomes responsive to signalling faster than its sibling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Paridaen, J. T., Wilsch-Brauninger, M. & Huttner, W. B. Asymmetric inheritance of centrosome-associated primary cilium membrane directs ciliogenesis after cell division. Cell 155, 333–344 (2013). This study demonstrates that a ciliary membrane remnant remains associated with the centrosome around the mother centriole after cilia disassembly to allow asymmetric ciliation and signalling competency in the daughter that inherits it.

    Article  CAS  PubMed  Google Scholar 

  173. 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.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Ho, E. K., Tsai, A. E. & Stearns, T. Transient primary cilia mediate robust hedgehog pathway-dependent cell cycle control. Curr. Biol. 30, 2829–2835.e5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Spear, P. C. & Erickson, C. A. Apical movement during interkinetic nuclear migration is a two-step process. Dev. Biol. 370, 33–41 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Ho, E. K. & Stearns, T. Hedgehog signaling and the primary cilium: implications for spatial and temporal constraints on signaling. Development https://doi.org/10.1242/dev.195552 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Phua, S. C. et al. Dynamic remodeling of membrane composition drives cell cycle through primary cilia excision. Cell 168, 264–279.e15 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Airik, M. et al. Loss of Anks6 leads to YAP deficiency and liver abnormalities. Hum. Mol. Genet. 29, 3064–3080 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Grisham, J. W. Ciliated epithelial cells in normal murine intrahepatic bile ducts. Proc. Soc. Exp. Biol. Med. 114, 318–320 (1963).

    Article  CAS  PubMed  Google Scholar 

  180. Tanuma, Y. & Ohata, M. Occurrence of centrioles in interphasic hepatocytes of bat and chicken. Arch. Histol. Jpn. 41, 377–384 (1978).

    Article  CAS  PubMed  Google Scholar 

  181. Hirose, Y., Itoh, T. & Miyajima, A. Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells. Exp. Cell Res. 315, 2648–2657 (2009).

    Article  CAS  PubMed  Google Scholar 

  182. Grzelak, C. A. et al. The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury. J. Hepatol. 60, 143–151 (2014).

    Article  CAS  PubMed  Google Scholar 

  183. Masyuk, A. I. et al. Cholangiocyte cilia detect changes in luminal fluid flow and transmit them into intracellular Ca2+ and cAMP signaling. Gastroenterology 131, 911–920 (2006).

    Article  CAS  PubMed  Google Scholar 

  184. Gradilone, S. A. et al. Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretion. Proc. Natl Acad. Sci. USA 104, 19138–19143 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. 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 

  186. Lam, W. Y. et al. Identification of a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia patients implicates ciliary dysfunction as a novel disease mechanism. EBioMedicine 71, 103530 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Rock, N. & McLin, V. Liver involvement in children with ciliopathies. Clin. Res. Hepatol. Gastroenterol. 38, 407–414 (2014).

    Article  CAS  PubMed  Google Scholar 

  188. Gradilone, S. A. et al. HDAC6 Inhibition restores ciliary expression and decreases tumor growth. Cancer Res. 73, 2259–2270 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. 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 

  190. Hilgendorf, K. I. et al. Omega-3 fatty acids activate ciliary FFAR4 to control adipogenesis. Cell 179, 1289–1305.e21 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. 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 

  192. Masyuk, A. I. et al. Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G990–G999 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Ma, M., Tian, X., Igarashi, P., Pazour, G. J. & Somlo, S. Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat. Genet. 45, 1004–1012 (2013). Using mouse genetics involving loss of polycystins and cilia in developing and adult kidney and liver, this study reveals a novel pathway that inhibits cystic growth, which is inhibited by polycystins and activated by cilia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Waddell, S. H. et al. Primary cilia loss promotes reactivation of morphogenesis and cyst-fission through a deregulated TGFβ-ECM-Integrin axis in polycystic liver disease. Preprint at bioRxiv https://doi.org/10.1101/2022.04.08.487546 (2022).

    Article  Google Scholar 

  195. Dong, K. et al. Renal plasticity revealed through reversal of polycystic kidney disease in mice. Nat. Genet. 53, 1649–1663 (2021). This study demonstrates that even late-stage ADPKD can be rescued by restoring either Pkd1 or Pkd2 gene function, highlighting high plasticity and reversibility of ciliopathic disease phenotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Pazour, G. J. & Witman, G. B. The vertebrate primary cilium is a sensory organelle. Curr. Opin. Cell Biol. 15, 105–110 (2003).

    Article  CAS  PubMed  Google Scholar 

  197. 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). This is the first study demonstrating that defects in IFT lead to aberrant assembly of primary cilia and cause ciliopathy (polycystic kidney disease) in vertebrates.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Haycraft, C. J., Swoboda, P., Taulman, P. D., Thomas, J. H. & Yoder, B. K. The C. elegans homolog of the murine cystic kidney disease gene Tg737 functions in a ciliogenic pathway and is disrupted in osm-5 mutant worms. Development 128, 1493–1505 (2001).

    Article  CAS  PubMed  Google Scholar 

  199. Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83 (2003). By performing a genetic screen in the mouse, this study is the first to show that mutations in IFT genes lead to aberrant Hedgehog signalling and cause severe developmental defects in vertebrates.

    Article  CAS  PubMed  Google Scholar 

  200. Olivieri, J. E. et al. RNA splicing programs define tissue compartments and cell types at single-cell resolution. eLife https://doi.org/10.7554/eLife.70692 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Yang, C. et al. Pre-mRNA processing factors and retinitis pigmentosa: RNA splicing and beyond. Front. Cell Dev. Biol. https://doi.org/10.3389/fcell.2021.700276 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Kwon, O. S. et al. Exon junction complex dependent mRNA localization is linked to centrosome organization during ciliogenesis. Nat. Commun. 12, 1351 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Haward, F. et al. Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function. eLife https://doi.org/10.7554/eLife.65104 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Geladaki, A. et al. Combining LOPIT with differential ultracentrifugation for high-resolution spatial proteomics. Nat. Commun. 10, 331 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Mund, A. et al. Deep Visual Proteomics defines single-cell identity and heterogeneity. Nat. Biotechnol. 40, 1231–1240 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Qin, W., Cho, K. F., Cavanagh, P. E. & Ting, A. Y. Deciphering molecular interactions by proximity labeling. Nat. Methods 18, 133–143 (2021).

    Article  CAS  PubMed  Google Scholar 

  207. Zhou, Y. et al. Expanding APEX2 substrates for proximity-dependent labeling of nucleic acids and proteins in living cells. Angew. Chem. Int. Ed. 58, 11763–11767 (2019).

    Article  CAS  Google Scholar 

  208. Truong, M. E. et al. Vertebrate cells differentially interpret ciliary and extraciliary cAMP. Cell 184, 2911–2926.e18 (2021). This study uses optogenetic and chemogenetic tools to show that cells distinguish between ciliary and extraciliary GPCR signalling via functionally and spatially distinct cAMP and PKA pools to control diverse cellular signalling processes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Hansen, J. N. et al. A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation. EMBO Rep. 23, e54315 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Sheu, S. H. et al. A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility. Cell 185, 3390–3407.e18 (2022). This study uses FIB-SEM of adult brain tissue to identify a novel ‘axociliary synapse’ where axons release serotonin directly onto cilia, acting as a shortcut for sending signals quickly and altering gene regulation in the nucleus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Bock, A. et al. Optical mapping of cAMP signaling at the nanometer scale. Cell 182, 1519–1530.e17 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Lelek, M. et al. Single-molecule localization microscopy. Nat. Rev. Methods Prim. 1, 39 (2021).

    Article  CAS  Google Scholar 

  213. Arsić, A., Hagemann, C., Stajković, N., Schubert, T. & Nikić-Spiegel, I. Minimal genetically encoded tags for fluorescent protein labeling in living neurons. Nat. Commun. 13, 314 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Satoda, Y. et al. BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1. Mol. Biol. Cell 33, ar79 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Shaheen, R. et al. Bi-allelic mutations in FAM149B1 cause abnormal primary cilium and a range of ciliopathy phenotypes in humans. Am. J. Hum. Genet. 104, 731–737 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Sanders, A. A. et al. KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome. Genome Biol. 16, 293 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Epting, D. et al. The ciliary transition zone protein TMEM218 synergistically interacts with the NPHP module and its reduced dosage leads to a wide range of syndromic ciliopathies. Hum. Mol. Genet. 31, 2295–2306 (2022).

    Article  CAS  PubMed  Google Scholar 

  218. Grinspon, R. P. Genetics of congenital central hypogonadism. Best. Pract. Res. Clin. Endocrinol. Metab. 36, 101599 (2022).

    Article  CAS  PubMed  Google Scholar 

  219. Tanaka, N. et al. Canine CNGA3 gene mutations provide novel insights into human achromatopsia-associated channelopathies and treatment. PLoS ONE 10, e0138943 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Schonauer, R. et al. Novel nephronophthisis-associated variants reveal functional importance of MAPKBP1 dimerization for centriolar recruitment. Kidney Int. 98, 958–969 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  221. David, O. et al. Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy. Clin. Genet. 98, 303–307 (2020).

    Article  CAS  PubMed  Google Scholar 

  222. Brancati, F. et al. Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome. Eur. J. Hum. Genet. 26, 1266–1271 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Guen, V. J. et al. STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis. Cell Cycle 15, 678–688 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Vasquez, S. S. V., van Dam, J. & Wheway, G. An updated SYSCILIA gold standard (SCGSv2) of known ciliary genes, revealing the vast progress that has been made in the cilia research field. Mol. Biol. Cell 32, br13 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Lahteenoja, L. et al. A novel frameshift variant in CEP78 associated with nonsyndromic retinitis pigmentosa, and a review of CEP78-related phenotypes. Ophthalmic Genet. 43, 152–158 (2022).

    Article  CAS  PubMed  Google Scholar 

  226. 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). This paper reports the first discovery of IFT using digital interference contrast microscopy of Chlamydomonas cilia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. van Dam, T. J. et al. Evolution of modular intraflagellar transport from a coatomer-like progenitor. Proc. Natl Acad. Sci. USA 110, 6943–6948 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Taschner, M. & Lorentzen, E. The Intraflagellar Transport Machinery. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a028092 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  229. 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 

  230. Craft, J. M., Harris, J. A., Hyman, S., Kner, P. & Lechtreck, K. F. Tubulin transport by IFT is upregulated during ciliary growth by a cilium-autonomous mechanism. J. Cell Biol. 208, 223–237 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Kubo, T. et al. Together, the IFT81 and IFT74 N-termini form the main module for intraflagellar transport of tubulin. J. Cell Sci. 129, 2106–2119 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. 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). By using Chlamydomonas as a model, this study demonstrates that the BBSome functions as a cargo adapter for certain membrane-associated and soluble ciliary proteins during retrograde IFT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. 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 

  234. Reilly, M. L. & Benmerah, A. Ciliary kinesins beyond IFT: cilium length, disassembly, cargo transport and signalling. Biol. Cell 111, 79–94 (2019).

    Article  PubMed  Google Scholar 

  235. Klena, N. & Pigino, G. Structural biology of cilia and intraflagellar transport. Annu. Rev. Cell Dev. Biol. https://doi.org/10.1146/annurev-cellbio-120219-034238 (2022).

    Article  PubMed  Google Scholar 

  236. Petriman, N. A. et al. Biochemically validated structural model of the 15-subunit intraflagellar transport complex IFT-B. EMBO J. 41, e112440 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Lacey, S. E., Foster, H. E. & Pigino, G. The molecular structure of IFT-A and IFT-B in anterograde intraflagellar transport trains. Nat. Struct. Mol. Biol. https://doi.org/10.1038/s41594-022-00905-5 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Yang, S. et al. Near-atomic structures of the BBSome reveal the basis for BBSome activation and binding to GPCR cargoes. eLife https://doi.org/10.7554/eLife.55954 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Singh, S. K., Gui, M., Koh, F., Yip, M. C. & Brown, A. Structure and activation mechanism of the BBSome membrane protein trafficking complex. eLife https://doi.org/10.7554/eLife.53322 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Klink, B. U., Gatsogiannis, C., Hofnagel, O., Wittinghofer, A. & Raunser, S. Structure of the human BBSome core complex. eLife https://doi.org/10.7554/eLife.53910 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors apologize to authors whose work could not be cited due to space and reference limitations. The authors thank A. Roberts and E. Lorentzen for helpful discussions and appreciate the very helpful comments and suggestions by the reviewers, which greatly improved this review. P.M. is grateful for support from the MRC (MC_U_12018/26) and from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement n°866355). S.T.C. is grateful for support from the Lundbeck Foundation (R317-2019-889), and L.B.P. acknowledges funding from the Novo Nordisk Foundation (grant #NNF18OC0053024) and Independent Research Fund Denmark (grant #2032-00115B).

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  1. These authors contributed equally: Pleasantine Mill, Søren T. Christensen.

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  1. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland

    Pleasantine Mill

  2. Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Søren T. Christensen & Lotte B. Pedersen

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Glossary

Axoneme

Core structure of cilia, which usually comprises 9 outer microtubule doublets and 0 or 2 central microtubule singlets in primary (9 + 0) and motile cilia (9 + 2), respectively.

Basal body

Specialized centriole that provides the foundation of the axoneme and anchors the cilium to the cell body via distal and subdistal appendages or fibres.

BBSome

A complex composed of eight Bardet–Biedl syndrome proteins, which is thought to function as a cargo adaptor for the retrograde IFT machinery during ciliary membrane protein export.

Centriole

Barrel-shaped structure composed of 9 microtubule triplets that gives rise to the basal body and constitutes the core structure of the centrosome.

Centrosome

Main microtubule-organizing centre in animals. Composed of two centrioles (mother and daughter) surrounded by pericentriolar material.

Ciliopathy

A genetic disorder characterized by ciliary dysfunction, and whose affected gene product localizes to (first-order ciliopathy) or indirectly affects (second-order ciliopathy) the cilium–centrosome axis.

Ciliary necklace

Outer aspect of the ciliary membrane located at the transition zone region where Y-links connect the inside of the membrane to the axoneme.

Ciliary pocket

An invagination of the periciliary membrane, which is a hotspot for endocytosis and exocytosis of vesicles derived from or destined to the ciliary membrane.

Ectosomes

Extracellular vesicles that bud directly from the membrane, including the ciliary membrane.

Intraflagellar transport

(IFT). Conserved intraciliary transport system in which kinesin 2 and cytoplasmic dynein 2 motors move trains of cargo-associated IFT-A/B complexes into and out of cilia. Required for ciliary assembly, maintenance and function.

Periciliary membrane

Membrane region at the base of the cilium that connects the ciliary membrane with the plasma membrane. Sometimes invaginated to form a ciliary pocket.

Phosphoinositides

(PIPs). Lipid signalling molecules that coordinate multiple membrane-associated molecular events.

Primary cilia

Non-motile sensory organelles present on the cell surface. They typically have a 9 + 0 axoneme surrounded by a membrane enriched for specific receptors and ion channels involved in signalling.

Transition zone

(TZ). Ciliary subcompartment located between the basal body and cilium itself, which functions as a barrier for selective transport of molecules into and out of the cilium.

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Mill, P., Christensen, S.T. & Pedersen, L.B. Primary cilia as dynamic and diverse signalling hubs in development and disease. Nat Rev Genet 24, 421–441 (2023). https://doi.org/10.1038/s41576-023-00587-9

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