Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The development and functions of multiciliated epithelia

Nature Reviews Molecular Cell Biology volume 18, pages 423–436 (2017)Cite this article

Subjects

Key Points

  • Multiciliated cells are derived from progenitor cells after the inhibition of Notch signalling and activation of two coiled-coil domain-containing proteins: geminin coiled-coil domain-containing protein 1 (GEMC1) and multicilin.

  • During multiciliated cell differentiation, tens of centrioles are produced by harnessing the signalling pathway that is used for canonical centriole duplication in dividing cells.

  • A combination of cytoskeletal networks, planar cell polarity pathways and mechanical forces are involved in the coordinated beating of multiple motile cilia.

  • Multiciliated cells fulfil diverse and crucial functions such as protection from external particles, active transport of materials and regulation of organ homeostasis.

Abstract

Multiciliated cells are epithelial cells that are in contact with bodily fluids and are required for the proper function of major organs including the brain, the respiratory system and the reproductive tracts. Their multiple motile cilia beat unidirectionally to remove particles of external origin from their surface and/or drive cells or fluids into the lumen of the organs. Multiciliated cells in the brain are produced once, almost exclusively during embryonic development, whereas in respiratory tracts and oviducts they regenerate throughout life. In this Review, we provide a cell-to-organ overview of multiciliated cells and highlight recent studies that have greatly increased our understanding of the mechanisms driving the development and function of these cells in vertebrates. We discuss cell fate determination and differentiation of multiciliated cells, and provide a comprehensive account of their locations and functions in mammals.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mammalian multiciliated cell fate determination.
Figure 2: Mammalian multiciliated cell differentiation.
Figure 3: Different kinds of planar cell polarity in multiciliated tissues.
Figure 4: Locations and proposed functions of multiciliated cells in the human body.

Similar content being viewed by others

References

  1. Tyler, S. Development of cilia in embryos of the turbellarian Macrostomum. Hydrobiologia 84, 231–239 (1981).

    Article  Google Scholar 

  2. Tamm, S. L. & Tamm, S. Development of macrociliary cells in Beroe. J. Cell Sci. 89, 81–95 (1988).

    PubMed  Google Scholar 

  3. Machemer, H. Ciliary activity and the origin of metachrony in Paramecium: effects of increased viscosity. J. Exp. Biol. 57, 239–259 (1972).

    CAS  PubMed  Google Scholar 

  4. Ishikawa, T. Axoneme structure from motile cilia. Cold Spring Harb. Perspect. Biol. 9, a028076 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Vertii, A., Hung, H.-F., Hehnly, H. & Doxsey, S. Human basal body basics. Cilia 5, 13 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Loreng, T. D. & Smith, E. F. The central apparatus of cilia and eukaryotic flagella. Cold Spring Harb. Perspect. Biol. 9, a028118 (2016).

    Article  CAS  Google Scholar 

  7. Stockinger, L. & Cireli, E. An up-to-now unknown way of centriole propagation. Z. Zellforsch. Mikrosk. Anat. 68, 733–740 (in German) (1965).

    Article  CAS  PubMed  Google Scholar 

  8. Steinman, R. M. An electron microscopic study of ciliogenesis in developing epidermis and trachea in the embryo of Xenopus laevis. Am. J. Anat. 122, 19–55 (1968).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Dirksen, E. R. Centriole morphogenesis in developing ciliated epithelium of the mouse oviduct. J. Cell Biol. 51, 286–302 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Anderson, R. & Brenner, R. The formation of basal bodies (centrioles) in the rhesus monkey oviduct. J. Cell Biol. 50, 10–34 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Verhage, H. G. & Brenner, R. M. Estradiol-induced differentiation of the oviductal epithelium in ovariectomized cats. Biol. Reprod. 13, 104–111 (1975).

    Article  CAS  PubMed  Google Scholar 

  13. Verhage, H. G., Bareither, M. L., Jaffe, R. C. & Akbar, M. Cyclic changes in ciliation, secretion and cell height of the oviductal epithelium in women. Am. J. Anat. 156, 505–521 (1979).

    Article  CAS  PubMed  Google Scholar 

  14. Kalnins, V. I. & Porter, K. R. Centriole replication during ciliogenesis in the chick tracheal epithelium. Z. Zellforsch. Mikrosk. Anat. 100, 1–30 (1969).

    Article  CAS  PubMed  Google Scholar 

  15. Kalnins, V. I., Chung, C. K. & Turnbull, C. Procentrioles in ciliating and ciliated cells of chick trachea. Z. Zellforsch. Mikrosk. Anat. 135, 461–471 (1972).

    Article  CAS  PubMed  Google Scholar 

  16. Spassky, N. et al. Adult ependymal cells are postmitotic and are derived from radial glial cells during embryogenesis. J. Neurosci. 25, 10–18 (2005). References 7–16 describe centriole amplification in progenitors of multiciliated cells, mainly by using transmission electron microscopy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Vladar, E. K. & Stearns, T. Molecular characterization of centriole assembly in ciliated epithelial cells. J. Cell Biol. 178, 31–42 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Klos Dehring, D. A. et al. Deuterosome-mediated centriole biogenesis. Dev. Cell 27, 103–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Zhao, H. et al. The Cep63 paralogue Deup1 enables massive de novo centriole biogenesis for vertebrate multiciliogenesis. Nat. Cell Biol. 15, 1434–1444 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Al Jord, A. et al. Centriole amplification by mother and daughter centrioles differs in multiciliated cells. Nature 516, 104–107 (2014). References 17–20 show that a comparable signalling pathway is used for centriole amplification in progenitors of multiciliated cells and for centrosome duplication during the cell cycle.

    Article  CAS  PubMed  Google Scholar 

  21. Mirzadeh, Z., Han, Y.-G., Soriano-Navarro, M., García-Verdugo, J. M. & Alvarez-Buylla, A. Cilia organize ependymal planar polarity. J. Neurosci. 30, 2600–2610 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Masterton, R., Armstrong, E. M. & More, I. A. The cyclical variation in the percentage of ciliated cells in the normal human endometrium. J. Reprod. Fertil. 42, 537–540 (1974).

    Article  Google Scholar 

  23. Kessler, M. et al. The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nat. Commun. 6, 8989 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Rock, J. R. et al. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc. Natl Acad. Sci. USA 106, 12771–12775 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Daniely, Y. et al. Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium. Am. J. Physiol. Cell Physiol. 287, C171–C181 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Que, J., Luo, X., Schwartz, R. J. & Hogan, B. L. M. Multiple roles for Sox2 in the developing and adult mouse trachea. Development 136, 1899–1907 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hogan, B. L. M. et al. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15, 123–138 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rock, J. R. & Hogan, B. L. M. Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu. Rev. Cell Dev. Biol. 27, 493–512 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Luo, J., Shook, B. A., Daniels, S. B. & Conover, J. C. Subventricular zone-mediated ependyma repair in the adult mammalian brain. J. Neurosci. 28, 3804–3813 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Luo, Y. et al. Single-cell transcriptome analyses reveal signals to activate dormant neural stem cells. Cell 161, 1175–1188 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fuentealba, L. C. et al. Embryonic origin of postnatal neural stem cells. Cell 161, 1644–1655 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liu, Y., Pathak, N., Kramer-Zucker, A. & Drummond, I. A. Notch signaling controls the differentiation of transporting epithelia and multiciliated cells in the zebrafish pronephros. Development 134, 1111–1122 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Marcet, B. et al. Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway. Nat. Cell Biol. 13, 693–699 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Morimoto, M. et al. Canonical Notch signaling in the developing lung is required for determination of arterial smooth muscle cells and selection of Clara versus ciliated cell fate. J. Cell Sci. 123, 213–224 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mori, M. et al. Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. Development 142, 258–267 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stubbs, J. L., Vladar, E. K., Axelrod, J. D. & Kintner, C. Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation. Nat. Cell Biol. 14, 140–147 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Morimoto, M., Nishinakamura, R., Saga, Y. & Kopan, R. Different assemblies of Notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells. Development 139, 4365–4373 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Deblandre, G. A., Wettstein, D. A., Koyano-Nakagawa, N. & Kintner, C. A two-step mechanism generates the spacing pattern of the ciliated cells in the skin of Xenopus embryos. Development 126, 4715–4728 (1999).

    CAS  PubMed  Google Scholar 

  39. Guseh, J. S. et al. Notch signaling promotes airway mucous metaplasia and inhibits alveolar development. Development 136, 1751–1759 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tsao, P.-N. et al. Notch signaling controls the balance of ciliated and secretory cell fates in developing airways. Development 136, 2297–2307 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gomi, K., Arbelaez, V., Crystal, R. G. & Walters, M. S. Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway. PLoS ONE 10, e0116507 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Rawlins, E. L. et al. The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4, 525–534 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Watson, J. K. et al. Clonal dynamics reveal two distinct populations of basal cells in slow-turnover airway epithelium. Cell Rep. 12, 90–101 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pardo-Saganta, A. et al. Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations. Cell Stem Cell 16, 184–197 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pardo-Saganta, A. et al. Parent stem cells can serve as niches for their daughter cells. Nature 523, 597–601 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lafkas, D. et al. Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung. Nature 528, 127–131 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Kyrousi, C. et al. Mcidas and GemC1/Lynkeas are key regulators for the generation of multiciliated ependymal cells in the adult neurogenic niche. Development 44, 3661–3674 (2015). References 23, 32–41 and 47 show that inhibition of Notch controls the balance between specification into ciliated cells or into other cell types in different organs and species.

    Article  CAS  Google Scholar 

  48. Cibois, M. et al. BMP signalling controls the construction of vertebrate mucociliary epithelia. Development 142, 2352–2363 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Tadokoro, T. et al. IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells. Proc. Natl Acad. Sci. USA 111, E3641–E3699 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nishimura, Y. et al. Ciliated cells differentiated from mouse embryonic stem cells. Stem Cells 24, 1381–1388 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Nishimura, Y. et al. Inhibitory Smad proteins promote the differentiation of mouse embryonic stem cells into ependymal-like ciliated cells. Biochem. Biophys. Res. Commun. 401, 1–6 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Balestrini, A., Cosentino, C., Errico, A., Garner, E. & Costanzo, V. GEMC1 is a TopBP1-interacting protein required for chromosomal DNA replication. Nat. Cell Biol. 12, 484–491 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pefani, D. E. et al. Idas, a novel phylogenetically conserved geminin-related protein, binds to geminin and is required for cell cycle progression. J. Biol. Chem. 286, 23234–23246 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Caillat, C. et al. The Geminin and Idas coiled coils preferentially form a heterodimer that inhibits Geminin function in DNA replication licensing. J. Biol. Chem. 288, 31624–31634 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ma, L., Quigley, I., Omran, H. & Kintner, C. Multicilin drives centriole biogenesis via E2f proteins. Genes Dev. 28, 1461–1471 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Terré, B. et al. GEMC 1 is a critical regulator of multiciliated cell differentiation. EMBO J. 35, 942–960 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Arbi, M. et al. GemC1 controls multiciliogenesis in the airway epithelium. EMBO Rep. 17, 400–413 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Boon, M. et al. MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat. Commun. 5, 4418 (2014). References 36, 47, 55–57 and 60 show that GEMC1 and multicilin are the most upstream activators of the multiciliated cell programme.

  59. Tan, F. E. et al. Myb promotes centriole amplification and later steps of the multiciliogenesis program. Development 140, 4277–4286 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhou, F. et al. Gmnc is a master regulator of the multiciliated cell differentiation program. Curr. Biol. 25, 3267–3273 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Danielian, P. S. et al. E2f4 is required for normal development of the airway epithelium. Dev. Biol. 305, 564–576 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Danielian, P. S., Hess, R. A. & Lees, J. A. E2f4 and E2f5 are essential for the development of the male reproductive system. Cell Cycle 15, 250–260 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Song, R. et al. miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110. Nature 510, 115–120 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wu, J. et al. Two miRNA clusters, miR-34b/c and miR-449, are essential for normal brain development, motile ciliogenesis, and spermatogenesis. Proc. Natl Acad. Sci. USA 111, E2851–E2857 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mirzadeh, Z., Doetsch, F., Sawamoto, K., Wichterle, H. & Alvarez-Buylla, A. The subventricular zone en-face: wholemount staining and ependymal flow. J. Vis. Exp. http://dx.doi.org/10.3791/1938 (2010).

  66. Lavado, A. & Oliver, G. Six3 is required for ependymal cell maturation. Development 138, 5291–5300 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Paez-gonzalez, P. et al. Article Ank3-dependent SVZ niche assembly is required for the continued production of new neurons. Neuron 71, 61–75 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Park, R. et al. Yap is required for ependymal integrity and is suppressed in LPA-induced hydrocephalus. Nat. Commun. 7, 10329 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pan, J., You, Y., Huang, T. & Brody, S. L. RhoA-mediated apical actin enrichment is required for ciliogenesis and promoted by Foxj1. J. Cell Sci. 120, 1868–1876 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Sedzinski, J., Hannezo, E., Tu, F., Biro, M. & Wallingford, J. B. Emergence of an apical epithelial cell surface in vivo. Dev. Cell 36, 24–35 (2016). References 48, 69 and 70 identify the mechanisms required for morphological changes in the progenitors of multiciliated cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brown, N. J., Marjanovic, M., Lüders, J., Stracker, T. H. & Costanzo, V. Cep63 and Cep152 cooperate to ensure centriole duplication. PLoS ONE 8, e69986 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lukinavicˇius, G. et al. Selective chemical crosslinking reveals a Cep57-Cep63-Cep152 centrosomal complex. Curr. Biol. 23, 265–270 (2013).

    Article  CAS  Google Scholar 

  73. Sir, J.-H. et al. A primary microcephaly protein complex forms a ring around parental centrioles. Nat. Genet. 43, 1147–1153 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hoh, R. A., Stowe, T. R., Turk, E. & Stearns, T. Transcriptional program of ciliated epithelial cells reveals new cilium and centrosome components and links to human disease. PLoS ONE 7, e52166 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang, L. et al. miR-34b regulates multiciliogenesis during organ formation in zebrafish. Development 140, 2755–2764 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Funk, M. C. et al. Cyclin O (Ccno) functions during deuterosome-mediated centriole amplification of multiciliated cells. EMBO Rep. 34, 1078–1089 (2015).

    Article  CAS  Google Scholar 

  77. Meunier, A. & Spassky, N. Centriole continuity: out with the new, in with the old. Curr. Opin. Cell Biol. 38, 60–67 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Klein, H. C. R., Guichard, P., Hamel, V., Gönczy, P. & Schwarz, U. S. Computational support for a scaffolding mechanism of centriole assembly. Sci. Rep. 6, 27075 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ioannou, A., Santama, N. & Skourides, P. A. Xenopus laevis nucleotide binding protein 1 (xNubp1) is important for convergent extension movements and controls ciliogenesis via regulation of the actin cytoskeleton. Dev. Biol. 380, 243–258 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Guirao, B. et al. Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia. Nat. Cell Biol. 12, 341–350 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Wallmeier, J. et al. Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat. Genet. 46, 646–651 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Amirav, I. et al. Systematic analysis of CCNO variants in a defined population: implications for clinical phenotype and differential diagnosis. Hum. Mutat. 37, 396–405 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Casey, J. P. et al. Unexpected genetic heterogeneity for primary ciliary dyskinesia in the Irish Traveller population. Eur. J. Hum. Genet. 23, 210–217 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Lemullois, M., Boisvieux-Ulrich, E., Laine, M. C., Chailley, B. & Sandoz, D. Development and functions of the cytoskeleton during ciliogenesis in metazoa. Biol. Cell 63, 195–208 (1988).

    Article  CAS  PubMed  Google Scholar 

  85. Boisvieux-Ulrich, E., Lainé, M. C. & Sandoz, D. Cytochalasin D inhibits basal body migration and ciliary elongation in quail oviduct epithelium. Cell Tissue Res. 259, 443–454 (1990).

    Article  CAS  PubMed  Google Scholar 

  86. Gomperts, B. N., Gong-Cooper, X. & Hackett, B. P. Foxj1 regulates basal body anchoring to the cytoskeleton of ciliated pulmonary epithelial cells. J. Cell Sci. 117, 1329–1337 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Chevalier, B. et al. miR-34/449 control apical actin network formation during multiciliogenesis through small GTPase pathways. Nat. Commun. 6, 8386 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Antoniades, I., Stylianou, P. & Skourides, P. A. Making the connection: ciliary adhesion complexes anchor basal bodies to the actin cytoskeleton. Dev. Cell 28, 70–80 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Werner, M. E. et al. Actin and microtubules drive differential aspects of planar cell polarity in multiciliated cells. J. Cell Biol. 195, 19–26 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Miyatake, K., Kusakabe, M., Takahashi, C. & Nishida, E. ERK7 regulates ciliogenesis by phosphorylating the actin regulator CapZIP in cooperation with Dishevelled. Nat. Commun. 6, 6666 (2015). References 88–90 show the roles of the actin cytoskeleton in the apical migration and organization of basal bodies.

    Article  CAS  PubMed  Google Scholar 

  91. Park, T. J., Haigo, S. L. & Wallingford, J. B. Ciliogenesis defects in embryos lacking inturned or fuzzy function are associated with failure of planar cell polarity and Hedgehog signaling. Nat. Genet. 38, 303–311 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Park, T. J., Mitchell, B. J., Abitua, P. B., Kintner, C. & Wallingford, J. B. Dishevelled controls apical docking and planar polarization of basal bodies in ciliated epithelial cells. Nat. Genet. 40, 871–879 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gegg, M. et al. Flattop regulates basal body docking and positioning in mono- and multiciliated cells. eLife 3, e03842 (2014).

    Article  CAS  PubMed Central  Google Scholar 

  94. Gray, R. S. et al. The planar cell polarity effector Fuz is essential for targeted membrane trafficking, ciliogenesis, and mouse embryonic development. Nat. Cell Biol. 11, 1225–1232 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yasunaga, T. et al. The polarity protein inturned links NPHP4 to daam1 to control the subapical actin network in multiciliated cells. J. Cell Biol. 211, 963–973 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tissir, F. et al. Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus. Nat. Neurosci. 13, 700–707 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. Boutin, C. et al. A dual role for planar cell polarity genes in ciliated cells. Proc. Natl Acad. Sci. USA 111, E3129–E3138 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mitchell, B. et al. The PCP pathway instructs the planar orientation of ciliated cells in the Xenopus larval skin. Curr. Biol. 19, 924–929 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Boisvieux-Ulrich, E., Laine, M. C. & Sandoz, D. In vitro effects of taxol on ciliogenesis in quail oviduct. J. Cell Sci. 92, 9–20 (1989).

    PubMed  Google Scholar 

  100. Wei, Q., Ling, K. & Hu, J. The essential roles of transition fibers in the context of cilia. Curr. Opin. Cell Biol. 35, 98–105 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Burke, M. C. et al. Chibby promotes ciliary vesicle formation and basal body docking during airway cell differentiation. J. Cell Biol. 207, 123–137 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. El Zein, L. et al. RFX3 governs growth and beating efficiency of motile cilia in mouse and controls the expression of genes involved in human ciliopathies. J. Cell Sci. 122, 3180–3189 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Chung, M. I. et al. RFX2 is broadly required for ciliogenesis during vertebrate development. Dev. Biol. 363, 155–165 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Chung, M. I. et al. Coordinated genomic control of ciliogenesis and cell movement by RFX2. eLife 3, e01439 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Choksi, S. P., Lauter, G., Swoboda, P. & Roy, S. Switching on cilia: transcriptional networks regulating ciliogenesis. Development 141, 1427–1441 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Chen, J., Knowles, H. J., Hebert, J. L. & Hackett, B. P. Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry. J. Clin. Invest. 102, 1077–1082 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Brody, S. L., Yan, X. H., Wuerffel, M. K., Song, S. & Shapiro, S. D. Ciliogenesis and left–right axis defects in forkhead factor HFH-4 – null mice (aka FOXJ1 mutant mice). Am. J. Respir. Cell Mol. Biol. 23, 45–51 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Yu, X., Ng, C. P., Habacher, H. & Roy, S. Foxj1 transcription factors are master regulators of the motile ciliogenic program. Nat. Genet. 40, 1445–1453 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Didon, L. et al. RFX3 modulation of FOXJ1 regulation of cilia genes in the human epithelium. Respir. Res. 14, 70 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tözser, J. et al. TGF-β signaling regulates the differentiation of motile cilia. Cell Rep. 11, 1000–1007 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. 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 

  112. Nemajerova, A. et al. TAp73 is a central transcriptional regulator of airway multiciliogenesis. Genes Dev. 30, 1300–1312 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Marshall, C. B. et al. P73 is required for multiciliogenesis and regulates the Foxj1-associated gene network. Cell Rep. 14, 2289–2300 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gonzalez-Cano, L. et al. p73 is required for ependymal cell maturation and neurogenic SVZ cytoarchitecture Abbreviated. Dev. Neurobiol. 76, 730–747 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Singh, J. & Mlodzik, M. Planar cell polarity signaling: coordination of cellular orientation across tissues. Wiley Interdiscip. Rev. Dev. Biol. 1, 479–499 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Vladar, E. K., Bayly, R. D., Sangoram, A. M., Scott, M. P. & Axelrod, J. D. Microtubules enable the planar cell polarity of airway cilia. Curr. Biol. 22, 2203–2212 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ohata, S. et al. Loss of dishevelleds disrupts planar polarity in ependymal motile cilia and results in hydrocephalus. Neuron 83, 558–571 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Shi, D. et al. Dynamics of planar cell polarity protein Vangl2 in the mouse oviduct epithelium. Mech. Dev. 141, 78–89 (2016). References 80, 88–98 and 116–118 show the roles of PCP genes in the planar orientation of multiciliated cells.

    Article  CAS  PubMed  Google Scholar 

  119. Qian, D. et al. Wnt5a functions in planar cell polarity regulation in mice. Dev. Biol. 306, 121–133 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Gros, J., Serralbo, O. & Marcelle, C. WNT11 acts as a directional cue to organize the elongation of early muscle fibres. Nature 457, 589–593 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Gao, B. et al. Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2. Dev. Cell 20, 163–176 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ohata, S. et al. Mechanosensory genes Pkd1 and Pkd2 contribute to the planar polarization of brain ventricular epithelium. J. Neurosci. 35, 11153–11168 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Chien, Y. H., Keller, R., Kintner, C. & Shook, D. R. Mechanical strain determines the axis of planar polarity in ciliated epithelia. Curr. Biol. 25, 2774–2784 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mitchell, B., Jacobs, R., Li, J., Chien, S. & Kintner, C. A positive feedback mechanism governs the polarity and motion of motile cilia. Nature 447, 97–101 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Chien, Y.-H. et al. Bbof1 is required to maintain cilia orientation. Development 140, 3468–3477 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lechtreck, K.-F., Delmotte, P., Robinson, M. L., Sanderson, M. J. & Witman, G. B. Mutations in Hydin impair ciliary motility in mice. J. Cell Biol. 180, 633–643 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Matsuo, M., Shimada, A., Koshida, S., Saga, Y. & Takeda, H. The establishment of rotational polarity in the airway and ependymal cilia: analysis with a novel cilium motility mutant mouse. Am. J. Physiol. Lung Cell. Mol. Physiol. 304, L736–L745 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Sandoz, D. et al. Organization and functions of cytoskeleton in metazoan ciliated cells. Biol. Cell 63, 183–193 (1988).

    Article  CAS  PubMed  Google Scholar 

  129. Hagiwara, H., Kano, A., Aoki, T., Ohwada, N. & Takata, K. Localization of gamma-tubulin to the basal foot associated with the basal body extending a cilium. Histochem. J. 32, 669–671 (2000).

    Article  CAS  PubMed  Google Scholar 

  130. Kunimoto, K. et al. Coordinated ciliary beating requires Odf2-mediated polarization of basal bodies via basal feet. Cell 148, 189–200 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. Herawati, E. et al. Multiciliated cell basal bodies align in stereotypical patterns coordinated by the apical cytoskeleton. J. Cell Biol. 214, 571–586 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Clare, D. K. et al. Basal foot MTOC organizes pillar MTs required for coordination of beating cilia. Nat. Commun. 5, 4888 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Ying, G. et al. Centrin 2 is required for mouse olfactory ciliary trafficking and development of ependymal cilia planar polarity. J. Neurosci. 34, 6377–6388 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Teves, M. E. et al. Sperm-associated antigen 6 (SPAG6) deficiency and defects in ciliogenesis and cilia function: polarity, density, and beat. PLoS ONE 9, e107271 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Hegan, P. S., Ostertag, E., Geurts, A. M. & Mooseker, M. S. Myosin Id is required for planar cell polarity in ciliated tracheal and ependymal epithelial cells. Cytoskeleton (Hoboken) 72, 503–516 (2015).

    Article  CAS  Google Scholar 

  136. Hirota, Y. et al. Planar polarity of multiciliated ependymal cells involves the anterior migration of basal bodies regulated by non-muscle myosin II. Development 137, 3037–3046 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Guirao, B. & Joanny, J.-F. Spontaneous creation of macroscopic flow and metachronal waves in an array of cilia. Biophys. J. 92, 1900–1917 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Elgeti, J. & Gompper, G. Emergence of metachronal waves in cilia arrays. Proc. Natl Acad. Sci. USA 110, 4470–4475 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Workman, A. D. & Cohen, N. A. The effect of drugs and other compounds on the ciliary beat frequency of human respiratory epithelium. Am. J. Rhinol. Allergy 28, 454–464 (2014).

    Article  PubMed  Google Scholar 

  140. Shah, A. S., Ben-Shahar, Y., Moninger, T. O., Kline, J. N. & Welsh, M. J. Motile cilia of human airway epithelia are chemosensory. Science 325, 1131–1134 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Andrade, Y. N. et al. TRPV4 channel is involved in the coupling of fluid viscosity changes to epithelial ciliary activity. J. Cell Biol. 168, 869–874 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Button, B. M. & Button, B. Structure and function of the mucus clearance system of the lung. Cold Spring Harb. Perspect. Med. 3, a009720 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. O'Callaghan, C. L., Sikand, K., Rutman, A. & Hirst, R. A. The effect of viscous loading on brain ependymal cilia. Neurosci. Lett. 439, 56–60 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Wodarczyk, C. et al. A novel mouse model reveals that polycystin-1 deficiency in ependyma and choroid plexus results in dysfunctional cilia and hydrocephalus. PLoS ONE 4, e7137 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Jain, R. et al. Sensory functions of motile cilia and implication for bronchiectasis. Front. Biosci. (Schol. Ed.) 4, 1088–1098 (2012).

    Google Scholar 

  146. Gudis, D., Zhao, K. Q. & Cohen, N. A. Acquired cilia dysfunction in chronic rhinosinusitis. Am. J. Rhinol. Allergy 26, 1–6 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Laoukili, J. et al. IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. J. Clin. Invest. 108, 1817–1824 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Papathanasiou, A., Djahanbakhch, O., Saridogan, E. & Lyons, R. A. The effect of interleukin-6 on ciliary beat frequency in the human fallopian tube. Fertil. Steril. 90, 391–394 (2008).

    Article  CAS  PubMed  Google Scholar 

  149. Bylander, A. et al. Rapid effects of progesterone on ciliary beat frequency in the mouse fallopian tube. Reprod. Biol. Endocrinol. 8, 48 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Nguyen, T., Chin, W. C., O'Brien, J. A., Verdugo, P. & Berger, A. J. Intracellular pathways regulating ciliary beating of rat brain ependymal cells. J. Physiol. 531, 131–140 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Conductier, G. et al. Melanin-concentrating hormone regulates beat frequency of ependymal cilia and ventricular volume. Nat. Neurosci. 16, 845–847 (2013).

    Article  CAS  PubMed  Google Scholar 

  152. Fahy, J. V. & Dickey, B. F. Airway mucus function and dysfunction. N. Engl. J. Med. 363, 2233–2247 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ganz, T. Antimicrobial polypeptides in host defense of the respiratory tract. J. Clin. Invest. 109, 693–697 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Knowles, M. R. & Boucher, R. C. Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Invest. 109, 571–577 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Tremble, E. Further observations of nasal cilia. Laryngoscope 63, 619–631 (1953).

    Article  CAS  PubMed  Google Scholar 

  156. Toskala, E., Smiley-Jewell, S. M., Wong, V. J., King, D. & Plopper, C. G. Temporal and spatial distribution of ciliogenesis in the tracheobronchial airways of mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 289, L454–L459 (2005).

    Article  CAS  PubMed  Google Scholar 

  157. Mercer, R. R., Russell, M. L., Roggli, V. L. & Crapo, J. D. Cell number and distribution in human and rat airways. Am. J. Respir. Cell Mol. Biol. 10, 613–624 (1994).

    Article  CAS  PubMed  Google Scholar 

  158. Jones, N. The nose and paranasal sinuses. Adv. Drug Deliv. Rev. 51, 5–19 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Morrison, E. & Costanzo, R. Morphology of the human olfactory epithelium. J. Comp. Neurol. 297, 1–13 (1990).

    Article  CAS  PubMed  Google Scholar 

  160. Hentzer, E. Ultrastructure of the middle ear mucosa. Acta Otolaryngol. Suppl. 414, 19–27 (1984).

    Article  CAS  PubMed  Google Scholar 

  161. Lim, D. J. Functional morphology of the tubotympanum. An overview. Acta Otolaryngol. Suppl. 414, 13–18 (1984).

    Article  CAS  PubMed  Google Scholar 

  162. Sade, J. Ciliary activity and middle ear clearance. Arch. Otolaryngol. 86, 128–135 (1967).

    Article  CAS  PubMed  Google Scholar 

  163. Li, X. et al. Otitis media in sperm-associated antigen 6 (Spag6)-deficient mice. PLoS ONE 9, 2–9 (2014).

    Google Scholar 

  164. Morgan, L. C. & Birman, C. S. The impact of primary ciliary dyskinesia on the upper respiratory tract. 18, 33–38 (2016).

  165. Button, B. et al. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science 337, 937–941 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Button, B., Okada, S. F., Frederick, C. B., Thelin, W. R. & Boucher, R. C. Mechanosensitive ATP release maintains proper mucus hydration of airways. Sci. Signal. 6, ra46 (2013).

    PubMed  PubMed Central  Google Scholar 

  167. Reiten, I. et al. Motile-cilia-mediated flow improves sensitivity and temporal resolution of olfactory computations. Curr. Biol. 27, 166–174 (2016).

    Article  PubMed  CAS  Google Scholar 

  168. Hafez, E. S., Ludwig, H. & Metzger, H. Human endometrial fluid kinetics as observed by scanning electron microscopy. Am. J. Obstet. Gynecol. 122, 929–938 (1975).

    Article  CAS  PubMed  Google Scholar 

  169. Amso, N. N., Crow, J., Lewin, J. & Shaw, R. W. A comparative morphological and ultrastructural study of endometrial gland and fallopian tube epithelia at different stages of the menstrual cycle and the menopause. Hum. Reprod. 9, 2234–2241 (1994).

    Article  CAS  PubMed  Google Scholar 

  170. Ludwig, H. & Metzger, H. The re-epithelization of endometrium after menstrual desquamation. Arch. Gynakol. 221, 51–60 (1976).

    Article  CAS  PubMed  Google Scholar 

  171. Donnez, J., Casanas-Roux, F., Caprasse, J., Ferin, J. & Thomas, K. Cyclic changes in ciliation, cell height, and mitotic activity in human tubal epithelium during reproductive life. Fertil. Steril. 43, 554–559 (1985).

    Article  CAS  PubMed  Google Scholar 

  172. Crow, J., Amso, N. N., Lewin, J. & Shaw, R. W. Morphology and infrastructure of Fallopian tube epithelium at different stages of the menstrual cycle and menopause. Hum. Reprod. 9, 2224–2233 (1994).

    Article  CAS  PubMed  Google Scholar 

  173. Patek, E., Nilsson, L. & Johannisson, E. Scanning electron microscopic study of the human fallopian tube. Report, I. The proliferative and secretory stages. Fertil. Steril. 23, 549–565 (1972).

    CAS  PubMed  Google Scholar 

  174. Brosens, I. A. & Vasquez, G. Fimbrial microbiopsy. J. Reprod. Med. 16, 171–178 (1976).

    CAS  PubMed  Google Scholar 

  175. Critoph, F. N. & Dennis, K. J. Ciliary activity in the human oviduct. Br. J. Obstet. Gynaecol. 84, 216–218 (1977).

    Article  CAS  PubMed  Google Scholar 

  176. Halbert, S. A., Tam, P. Y. & Blandau, R. J. Egg transport in the rabbit oviduct: the roles of cilia and muscle. Science 191, 1052–1053 (1976). Reference 176 shows that ciliary beating is required for oocyte transport in the oviduct.

    Article  CAS  PubMed  Google Scholar 

  177. Norwood, J. T. & Anderson, R. G. Evidence that adhesive sites on the tips of oviduct cilia membranes are required for ovum pickup in situ. Biol. Reprod. 23, 788–791 (1980).

    Article  CAS  PubMed  Google Scholar 

  178. Dirksen, E. R. & Satir, P. Ciliary activity in the mouse oviduct as studied by transmission and scanning electron microscopy. Tissue Cell 4, 389–404 (1972).

    Article  CAS  PubMed  Google Scholar 

  179. Lyons, R. A. et al. Fallopian tube ciliary beat frequency in relation to the stage of menstrual cycle and anatomical site. Hum. Reprod. 17, 584–588 (2002).

    Article  CAS  PubMed  Google Scholar 

  180. Lyons, R. A., Saridogan, E. & Djahanbakhch, O. The effect of ovarian follicular fluid and peritoneal fluid on Fallopian tube ciliary beat frequency. Hum. Reprod. 21, 52–56 (2006).

    Article  CAS  PubMed  Google Scholar 

  181. Wilcox, A. J., Weinberg, C. R. & Baird, D. B. Timing of sexual intercourse in relation to ovulation. N. Engl. J. Med. 333, 7–11 (1995).

    Article  Google Scholar 

  182. Holt, W. V. & Fazeli, A. Sperm storage in the female reproductive tract. Annu. Rev. Anim. Biosci. 4, 291–310 (2016).

    Article  PubMed  Google Scholar 

  183. Williams, M. et al. Sperm numbers and distribution within the human fallopian tube around ovulation. Hum. Reprod. 8, 2019–2026 (1993).

    Article  CAS  PubMed  Google Scholar 

  184. Motta, P. & Van Blerkom, J. A scanning electron microscopic study of rabbit spermatozoa in the female reproductive tract following coitus. Cell Tissue Res. 163, 29–44 (1975).

    Article  CAS  PubMed  Google Scholar 

  185. Pacey, A. A. et al. Andrology: the interaction in vitro of human spermatozoa with epithelial cells from the human uterine (Fallopian) tube. Hum. Reprod 10, 360–366 (1995).

    Article  CAS  PubMed  Google Scholar 

  186. Vigil, P., Salgado, A. M. & Cortés, M. E. Ultrastructural interaction between spermatozoon and human oviductal cells in vitro. J. Electron. Microsc. (Tokyo) 61, 123–126 (2012).

    Article  Google Scholar 

  187. Kervancioglu, E. M., Saridogan, E., John Aitken, R. & Djahanbakhch, O. Importance of sperm-to-epithelial cell contact for the capacitation of human spermatozoa in fallopian tube epithelial cell cocultures. Fertil. Steril. 74, 780–784 (2000).

    Article  CAS  PubMed  Google Scholar 

  188. Morales, P., Palma, V., Salgado, A. M. & Villalon, M. Sperm interaction with human oviductal cells in vitro. Hum. Reprod. 11, 1504–1509 (1996).

    Article  CAS  PubMed  Google Scholar 

  189. Fazeli, A., Duncan, A. E., Watson, P. F. & Holt, W. V. Sperm-oviduct interaction: Induction of capacitation and preferential binding of uncapacitated spermatozoa to oviductal epithelial cells in porcine species. Biol. Reprod. 60, 879–886 (1999).

    Article  CAS  PubMed  Google Scholar 

  190. Lefebvre, R. et al. Characterization of the oviductal sperm reservoir in cattle. Biol. Reprod. 53, 1066–1074 (1995).

    Article  CAS  PubMed  Google Scholar 

  191. Ilio, K. Y. & Hess, R. A. Structure and function of the ductuli efferentes: a review. Microsc. Res. Tech. 29, 432–467 (1994).

    Article  CAS  PubMed  Google Scholar 

  192. Ford, J. J., Carnes, K. & Hess, R. A. Ductuli efferentes of the male Golden Syrian hamster reproductive tract. Andrology 2, 510–520 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Yeung, C. H., Cooper, T. G., Bergmann, M. & Schulze, H. Organization of tubules in the human caput epididymidis and the ultrastructure of their epithelia. Am. J. Anat. 191, 261–279 (1991).

    Article  CAS  PubMed  Google Scholar 

  194. Hess, R. in The Epididymis: From Molecules to Clinical Practice (eds Robaire, B. & Hinton, B. T.) 49–80 (2002).

    Book  Google Scholar 

  195. Sullivan, R. & Mieusset, R. The human epididymis: its function in sperm maturation. Hum. Reprod. Update 22, 574–587 (2016).

    Article  CAS  PubMed  Google Scholar 

  196. Winet, H. On the mechanism for flow in the efferent ducts fluid. J. Androl. 1, 304–311 (1980).

    Article  Google Scholar 

  197. Mason, K. & Shaver, S. Some functions of the caput epididymis. Ann. NY Acad. Sci. 55, 585–593 (1952).

    Article  CAS  PubMed  Google Scholar 

  198. Hargrove, J. L., MacIndoe, J. H. & Ellis, L. C. Testicular contractile cells and sperm transport. Fertil. Steril. 28, 1146–1157 (1977).

    Article  CAS  PubMed  Google Scholar 

  199. Talo, A. In-vitro spontaneous electrical activity of rat efferent ductules. J. Reprod. Fertil. 63, 17–20 (1981).

    Article  CAS  PubMed  Google Scholar 

  200. Lun, M. P., Monuki, E. S. & Lehtinen, M. K. Development and functions of the choroid plexus–cerebrospinal fluid system. Nat. Rev. Neurosci. 16, 445–457 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Worthington, W. C. & Cathcart, R. S. Ependymal cilia: distribution and activity in the adult human brain. Science 139, 221–222 (1963).

    Article  PubMed  Google Scholar 

  202. Worthington, W. C. & Cathcart, R. S. Ciliary currents on ependymal surfaces. Ann. NY Acad. Sci. 130, 944–950 (1966).

    Article  PubMed  Google Scholar 

  203. Brinker, T., Stopa, E., Morrison, J. & Klinge, P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS 11, 10 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Hladky, S. B. & Barrand, M. A. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11, 26 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Siyahhan, B. et al. Flow induced by ependymal cilia dominates near-wall cerebrospinal fluid dynamics in the lateral ventricles. J. R. Soc. Interface 11, 20131189 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Faubel, R., Westendorf, C., Bodenschatz, E. & Eichele, G. Cilia-based flow network in the brain ventricles. Science 353, 176–178 (2016).

    Article  CAS  PubMed  Google Scholar 

  207. Kurtcuoglu, V., Poulikakos, D. & Ventikos, Y. Computational modeling of the mechanical behavior of the cerebrospinal fluid system. J. Biomech. Eng. 127, 264–269 (2005).

    Article  PubMed  Google Scholar 

  208. Kurtcuoglu, V. et al. Computational investigation of subject-specific cerebrospinal fluid flow in the third ventricle and aqueduct of Sylvius. J. Biomech. 40, 1235–1245 (2007).

    Article  PubMed  Google Scholar 

  209. Kurtcuoglu, V., Soellinger, M., Summers, P., Poulikakos, D. & Boesiger, P. Mixing and modes of mass transfer in the third cerebral ventricle: a computational analysis. J. Biomech. Eng. 129, 695–702 (2007). References 202 and 205–209 predict and/or show the complex macro- and microscale flow patterns that exist in brain ventricles and the involvement of ependymal ciliary beating in the formation of these patterns.

    Article  PubMed  Google Scholar 

  210. Sawamoto, K. et al. New neurons follow the flow of cerebrospinal fluid in the adult brain. Science 311, 629–632 (2006).

    Article  CAS  PubMed  Google Scholar 

  211. Kaneko, N. et al. New neurons clear the path of astrocytic processes for their rapid migration in the adult brain. Neuron 5, 213–223 (2010).

    Article  CAS  Google Scholar 

  212. Yamada, S. et al. Influence of respiration on cerebrospinal fluid movement using magnetic resonance spin labeling. Fluids Barriers CNS 10, 36 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Lehtinen, M. K. et al. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69, 893–905 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Mirzadeh, Z., Merkle, F. T., Soriano-Navarro, M., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell 3, 265–278 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Lim, D. A. et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28, 713–726 (2000).

    Article  CAS  PubMed  Google Scholar 

  216. Kokovay, E. et al. Adult SVZ lineage cells home to and leave the vascular niche via differential responses to SDF1/CXCR4 signaling. Cell Stem Cell 7, 163–173 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Ramírez-Castillejo, C. et al. Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat. Neurosci. 9, 331–339 (2006).

    Article  CAS  PubMed  Google Scholar 

  218. Andreu-Agulló, C., Morante-Redolat, J. M., Delgado, A. C. & Fariñas, I. Vascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone. Nat. Neurosci. 12, 1514–1523 (2009).

    Article  CAS  PubMed  Google Scholar 

  219. Sleight, M. Primary cilia dyskinesia. Lancet 318, 476 (1981).

    Article  Google Scholar 

  220. Fliegauf, M., Benzing, T. & Omran, H. When cilia go bad: cilia defects and ciliopathies. Nat. Rev. Mol. Cell Biol. 8, 880–893 (2007).

    Article  CAS  PubMed  Google Scholar 

  221. Horani, A., Ferkol, T. W., Dutcher, S. K. & Brody, S. L. Genetics and biology of primary ciliary dyskinesia. Paediatr. Respir. Rev. 18, 18–24 (2016).

    PubMed  Google Scholar 

  222. Barlocco, E. G. et al. Ultrastructural ciliary defects in children with recurrent infections of the lower respiratory tract. Pediatr. Pulmonol. 10, 11–17 (1991).

    Article  CAS  PubMed  Google Scholar 

  223. Berlucchi, M. et al. Ciliary aplasia associated with hydrocephalus: an extremely rare occurrence. Eur. Arch. Otorhinolaryngol. 269, 2295–2299 (2012).

    Article  PubMed  Google Scholar 

  224. Busquets, R. M., Caballero-Rabasco, M. A., Velasco, M., Lloreta, J. & García-Algar, Ó. Primary ciliary dyskinesia: clinical criteria indicating ultrastructural studies. Arch. Bronconeumol. 49, 99–104 (2013).

    Article  PubMed  Google Scholar 

  225. Carlén, B. & Stenram, U. Primary ciliary dyskinesia: a review. Ultrastruct. Pathol. 29, 217–220 (2005).

    Article  PubMed  Google Scholar 

  226. de Santi, M. M. et al. Cilia-lacking respiratory cells in ciliary aplasia. Biol. Cell 64, 67–70 (1988).

    Article  CAS  PubMed  Google Scholar 

  227. DeBoeck, K. et al. Aplasia of respiratory tract cilia. Pediatr. Pulmonol. 13, 259–265 (1992).

    Article  CAS  PubMed  Google Scholar 

  228. Engesaeth, V. G., Warner, J. O. & Bush, M. D. New associations of primary ciliary dyskinesia syndrome. Pediatr. Pulmonol. 16, 9–12 (1993).

    Article  CAS  PubMed  Google Scholar 

  229. Gordon, R. E. & Kattan, M. Absence of cilia and basal bodies with predominance of brush cells in the respiratory mucosa from a patient with immotile cilia syndrome. Ultrastruct. Pathol. 6, 45–49 (1984).

    Article  CAS  PubMed  Google Scholar 

  230. Gotz, M. & Stockinger, L. Aplasia of respiratory tract cilia. Lancet 321, 1283 (1983).

    Article  Google Scholar 

  231. Lungarella, G., de Santi, M. M., Palestri, R. & Tosi, P. Ultrastructural observations on basal apparatus of respiratory cilia in immotile cilia syndrome. Eur. J. Respir. Dis. 66, 165–172 (1985).

    CAS  PubMed  Google Scholar 

  232. De Santi, M. M., Magni, A., Valletta, E., Gardi, C. & Lungarella, G. Hydrocephalus, bronchiectasis, and ciliary aplasia. Arch. Dis. Child. 65, 543–544 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Maiti, A. et al. No deleterious mutations in the FOXJ1 (aliasHFH-4) gene in patients with primary ciliary dyskinesia (PCD). Cytogenet. Cell Genet. 90, 119–122 (2000).

    Article  CAS  PubMed  Google Scholar 

  234. Richard, S. et al. Congenital ciliary aplasia in two siblings. Pathol. Res. Pract. 185, 181–183 (1989).

    Article  CAS  PubMed  Google Scholar 

  235. Rodriguez Gil, Y., González, M. A. M. & Orradre, J. L. Ciliary hypoplasia: a rare cause of ciliary dyskinesia. Ultrastruct. Pathol. 30, 401–402 (2006).

    Article  Google Scholar 

  236. Wessels, M. W. et al. Candidate gene analysis in three families with acilia syndrome. Am. J. Med. Genet. A 146, 1765–1767 (2008).

    Article  Google Scholar 

  237. Babin, R. W. & Kavanagh, K. T. Familial nasal acilia syndrome. South. Med. J. 78, 737–739 (1985).

    Article  CAS  PubMed  Google Scholar 

  238. Matwijiw, I., Thliveris, J. A. & Faiman, C. Aplasia of nasal cilia with situs inversus, azoospermia and normal sperm flagella: a unique variant of the immotile cilia syndrome. J. Urol. 137, 522–524 (1987).

    Article  CAS  PubMed  Google Scholar 

  239. Cerezo, L. & Price, G. Absence of cilia and basal bodies with predominance of brush cells in the respiratory mucosa from a patient with immotile cilia syndrome. Ultrastruct. Pathol. 8, 381–382 (1985). References 58, 81–83 and 222–239 highlight cases of the under-studied ciliary aplasia phenotype.

    Article  CAS  PubMed  Google Scholar 

  240. Del Bigio, M. R. Ependymal cells: biology and pathology. Acta Neuropathol. 119, 55–73 (2010).

    Article  PubMed  Google Scholar 

  241. Greenstone, M. A., Jones, R. W., Dewar, A., Neville, B. G. & Cole, P. J. Hydrocephalus and primary ciliary dyskinesia. Arch. Dis. Child. 59, 481–482 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Ibañez-Tallon, I. et al. Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation. Hum. Mol. Genet. 13, 2133–2141 (2004).

    Article  PubMed  Google Scholar 

  243. Kosaki, K. et al. Absent inner dynein arms in a fetus with familial hydrocephalus-situs abnormality. Am. J. Med. Genet. A 129A, 308–311 (2004).

    Article  PubMed  Google Scholar 

  244. Rott, H. D. Kartagener's syndrome and the syndrome of immotile cilia. Hum. Genet. 46, 249–261 (1979).

    Article  CAS  PubMed  Google Scholar 

  245. Vieira, J. P., Lopes, P. & Silva, R. Primary ciliary dyskinesia and hydrocephalus with aqueductal stenosis. J. Child Neurol. 27, 938–941 (2012).

    Article  PubMed  Google Scholar 

  246. Picco, P. et al. Immotile cilia syndrome associated with hydrocephalus and precocious puberty: a case report. Eur. J. Pediatr. Surg. 3 (Suppl. 1), 20–21 (1993).

    PubMed  Google Scholar 

  247. Jabourian, Z. et al. Hydrocephalus in Kartagener's syndrome. Ear Nose Throat J. 65, 468–472 (1986).

    CAS  PubMed  Google Scholar 

  248. Wessels, M. W., den Hollander, N. S. & Willems, P. J. Mild fetal cerebral ventriculomegaly as a prenatal sonographic marker for Kartagener syndrome. Prenat. Diagn. 23, 239–242 (2003).

    Article  PubMed  Google Scholar 

  249. Greenstone, M., Rutman, A., Dewar, A., Mackay, I. & Cole, P. J. Primary ciliary dyskinesia: cytological and clinical features. Q. J. Med. 67, 405–423 (1988).

    CAS  PubMed  Google Scholar 

  250. Silverberg, G. D., Mayo, M., Saul, T., Rubenstein, E. & McGuire, D. Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol. 2, 506–511 (2003).

    Article  PubMed  Google Scholar 

  251. Johanson, C. E. et al. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res. 5, 10 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  252. Cruchaga, C. et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron 78, 256–268 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Keryer, G. et al. Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J. Clin. Invest. 121, 4372–4382 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Bleau, G., Richer, C. L. & Bousquet, D. Absence of dynein arms in cilia of endocervical cells in a fertile woman. Fertil. Steril. 30, 362–363 (1978).

    Article  CAS  PubMed  Google Scholar 

  256. Jean, Y., Langlais, J., Roberts, K. D., Chapdelaine, A. & Bleau, G. Fertility of a woman with nonfunctional ciliated cells in the fallopian tubes. Fertil. Steril. 31, 349–350 (1979).

    Article  CAS  PubMed  Google Scholar 

  257. Abu-Musa, A., Nassar, A. & Usta, I. In vitro fertilization in two patients with Kartagener's syndrome and infertility. Gynecol. Obstet. Invest. 65, 29–31 (2008).

    Article  PubMed  Google Scholar 

  258. Halbert, S. A., Patton, D. L., Zarutskie, P. W. & Soules, M. R. Function and structure of cilia in the fallopian tube of an infertile woman with Kartagener's syndrome. Hum. Reprod. 12, 55–58 (1997).

    Article  CAS  PubMed  Google Scholar 

  259. Lurie, M. et al. Ciliary ultrastructure of respiratory and fallopian tube epithelium in a sterile woman with Kartagener's syndrome. A quantitative estimation. Chest 95, 578–581 (1989).

    Article  CAS  PubMed  Google Scholar 

  260. McLean, L. & Claman, P. Chronic cough and infertility: a report of two cases. Fertil. Steril. 74, 1251–1253 (2000).

    Article  CAS  PubMed  Google Scholar 

  261. Pedersen, H. Absence of dynein arms in endometrial cilia: cause of infertility? Acta Obstet. Gynecol. Scand. 62, 625–627 (1983).

    Article  CAS  PubMed  Google Scholar 

  262. Lin, T. K. et al. A successful pregnancy with in vitro fertilization and embryo transfer in an infertile woman with Kartagener's syndrome: a case report. J. Assist. Reprod. Genet. 15, 625–627 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Afzelius, B. A. & Eliasson, R. Male and female infertility problems in the immotile-cilia syndrome. Eur. J. Respir. Dis. Suppl. 127, 144–147 (1983).

    CAS  PubMed  Google Scholar 

  264. Blyth, M. & Wellesley, D. Ectopic pregnancy in primary ciliary dyskinesia. J. Obstet. Gynaecol. 28, 358 (2008).

    Article  CAS  PubMed  Google Scholar 

  265. Knowles, M., Daniels, L., Davis, S., Zariwala, M. & Leigh, M. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am. J. Respir. Crit. Care Med. 188, 913–922 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Munkholm, M. & Mortensen, J. Mucociliary clearance: pathophysiological aspects. Clin. Physiol. Funct. Imaging 34, 171–177 (2014).

    Article  PubMed  Google Scholar 

  267. Katz, S. M. & Morgan, J. J. Cilia in the human kidney. Ultrastruct. Pathol. 6, 285–294 (1984).

    Article  CAS  PubMed  Google Scholar 

  268. Duffy, J. L. & Suzuki, Y. Ciliated human renal proximal tubular cells. Observations in three cases of hypercalcemia. Am. J. Pathol. 53, 609–616 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Ong, A. C. M. & Wagner, B. Detection of proximal tubular motile cilia in a patient with renal sarcoidosis associated with hypercalcemia. Am. J. Kidney Dis. 45, 1096–1099 (2005).

    Article  PubMed  Google Scholar 

  270. Datsis, S. A. & Boman, I. A. Ciliated renal tubular epithelium in congenital nephrosis. Beitr. Pathol. 151, 297–303 (1974).

    Article  CAS  PubMed  Google Scholar 

  271. Larsen, T. E. & Ghadially, F. N. Cilia in lupus nephritis. J. Pathol. 114, 69–73 (1974).

    Article  CAS  PubMed  Google Scholar 

  272. Lungarella, G., de Santi, M. M. & Tosi, P. Ultrastructural study of the ciliated cells from renal tubular epithelium in acute progressive glomerulonephritis. Ultrastruct. Pathol. 6, 1–7 (1984). References 267–272 show that multiciliated cells develop in the human kidney tubules in pathological situations.

    Article  CAS  PubMed  Google Scholar 

  273. Zecchi-Orlandini, S., Gulisano, M., Orlandini, G. E. & Holstein, A. F. Scanning electron microscopic observations on the epithelium of the human spongy urethra. Andrologia 20, 132–137 (1988).

    Article  CAS  PubMed  Google Scholar 

  274. Orlandini, G. E., Orlandini, S. Z., Holstein, A. F., Evangelisti, R. & Ponchietti, R. Scanning electron microscopic observations on the epithelium of the human prostatic urethra. Andrologia 19, 315–321 (1987).

    Article  CAS  PubMed  Google Scholar 

  275. Che, M., Ro, J. Y., Ordonez, N. G., Miller, R. W. & Ayala, A. G. Ciliated epithelia in the urethra: case report and literature review. Pathol. Int. 51, 892–895 (2001).

    Article  CAS  PubMed  Google Scholar 

  276. Johns, B A. et al. Developmental changes in the oesophageal epithelium in man. J. Anat. 86, 431–442.4 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Botha, G. Organogenesis and growth of the gastroesophageal region in man. Anat. Rec. 133, 219–239 (1959).

    Article  CAS  PubMed  Google Scholar 

  278. Ménard, D. & Arsenault, P. Maturation of human fetal esophagus maintained in organ culture. Anat. Rec. 217, 348–354 (1987).

    Article  PubMed  Google Scholar 

  279. Ivey, W. D. & Edgar, S. A. The histogenesis of the esophagus and crop of the chicken, turkey, guinea fowl and pigeaon, with special reference to ciliated epithelium. Anat. Rec. 114, 189–211 (1952).

    Article  CAS  PubMed  Google Scholar 

  280. Raymond, C., Anne, V. & Millane, G. Development of esophageal epithelium in the fetal and neonatal mouse. Anat. Rec. 230, 225–234 (1991). References 276–280 reveal the existence of a transient multiciliated epithelium in the fetal oesophagus of vertebrates.

    Article  CAS  PubMed  Google Scholar 

  281. Wells, J. M. & Melton, D. A. Vertebrate endoderm development. Annu. Rev. Cell Dev. Biol. 15, 393–410 (1999).

    Article  CAS  PubMed  Google Scholar 

  282. Alfaro-Cervello, C. et al. The adult macaque spinal cord central canal zone contains proliferative cells and closely resembles the human. J. Comp. Neurol. 522, 1800–1817 (2014).

    Article  PubMed  Google Scholar 

  283. Grimes, D. T. et al. Zebrafish models of idiopathic scoliosis link cerebrospinal fluid flow defects to spine curvature. Science 352, 1341–1344 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Ohtsuki, K. Scanning electron microscopic studies on rabbit's spinal cord by resin cracking method. Arch. Histol. Jpn 34, 405–415 (1972).

    Article  Google Scholar 

  285. Nakayama, Y. & Kohno, K. Number and polarity of the ependymal cilia in the central canal of some vertebrates. J. Neurocytol. 3, 449–458 (1974).

    Article  CAS  PubMed  Google Scholar 

  286. Tanaka, K. et al. Ciliary ultrastructure in two sisters with Kartagener's syndrome. Med. Mol. Morphol. 40, 34–39 (2007).

    Article  PubMed  Google Scholar 

  287. Juncos, C. et al. Situs inversus totalis — 2 case reports. Rev. Chil. Pediatr. 85, 344–350 (in Spanish) (2014).

    Article  Google Scholar 

  288. Evander, E., Arborelius, M., Jonson, B., Simonsson, B. G. & Svensson, G. Lung function and bronchial reactivity in six patients with immotile cilia syndrome. Eur. J. Respir. Dis. Suppl. 127, 137–143 (1983).

    CAS  PubMed  Google Scholar 

  289. Narita, K., Kawate, T., Kakinuma, N. & Takeda, S. Multiple primary cilia modulate the fluid transcytosis in choroid plexus epithelium. Traffic 11, 287–301 (2010).

    Article  CAS  PubMed  Google Scholar 

  290. Banizs, B. et al. Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus. Development 132, 5329–5339 (2005).

    Article  CAS  PubMed  Google Scholar 

  291. Li, L. et al. Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells. Nat. Cell Biol. 18, 418–430 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Dohrmann, G. J. & Bucy, P. C. Human choroid plexus: a light and electron microscopic study. J. Neurosurg. 33, 506–516 (1970).

    Article  CAS  PubMed  Google Scholar 

  293. Davis, D. A., Lloyd, B. J. Jr & Milhorat, T. H. A comparative ultrastructural study of the choroid plexuses of the immature pig. Anat. Rec. 176, 443–454 (1973).

    Article  CAS  PubMed  Google Scholar 

  294. Doolin, P. F. & Birge, W. J. Ultrastructural organization of cilia and basal bodies of the epithelium of the choroid plexus in the chick embryo. J. Cell Biol. 29, 333–345 (1966).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Peters, A. & Swan, R. C. The choroid plexus of the mature and aging rat: the choroidal epithelium. Anat. Rec. 194, 325–353 (1979).

    Article  CAS  PubMed  Google Scholar 

  296. Santolaya, R. & Rodriguez Echandia, E. The surface of the choroid plexus cell under normal and experimental conditions. Z. Zellforsch. Mikrosk. Anat. 92, 43–51 (1968).

    Article  CAS  PubMed  Google Scholar 

  297. Swiderski, R. E. et al. Structural defects in cilia of the choroid plexus, subfornical organ and ventricular ependyma are associated with ventriculomegaly. Fluids Barriers CNS 9, 22 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  298. Narita, K. et al. Proteomic analysis of multiple primary cilia reveals a novel mode of ciliary development in mammals. Biol. Open 1, 815–825 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. 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 (Hoboken) 70, 797–803 (2013).

    Article  CAS  Google Scholar 

  300. Mirzadeh, Z. et al. Bi− and uniciliated ependymal cells define continuous floor-plate-derived tanycytic territories. Nat. Commun. 8, 13759 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Alfaro-Cervello, C., Soriano-Navarro, M., Mirzadeh, Z., Alvarez-Buylla, A. & Garcia-Verdugo, J. M. Biciliated ependymal cell proliferation contributes to spinal cord growth. J. Comp. Neurol. 520, 3528–3552 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  302. Meletis, K. et al. Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol. 6, 1494–1507 (2008).

    Article  CAS  Google Scholar 

  303. McEwen, D. P., Jenkins, P. M. & Martens, J. R. Olfactory cilia: our direct neuronal connection to the external world. Curr. Top. Dev. Biol. 85, 333–370 (2008).

    Article  CAS  PubMed  Google Scholar 

  304. Williams, C. L. et al. Direct evidence for BBSome-associated intraflagellar transport reveals distinct properties of native mammalian cilia. Nat. Commun. 5, 5813 (2014).

    Article  CAS  PubMed  Google Scholar 

  305. Challis, R. C. et al. An olfactory cilia pattern in the mammalian nose ensures high sensitivity to odors. Curr. Biol. 25, 2503–2512 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Moran, D. T., Rowley, J. C., Jafek, B. W. & Lovell, M. A. The fine structure of the olfactory mucosa in man. J. Neurocytol. 11, 721–746 (1982).

    Article  CAS  PubMed  Google Scholar 

  307. Tadenev, A. L. D. et al. Loss of Bardet-Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting. Proc. Natl Acad. Sci. USA 108, 10320–10325 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  308. Kulaga, H. M. et al. Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse. Nat. Genet. 36, 994–998 (2004).

    Article  CAS  PubMed  Google Scholar 

  309. McEwen, D. P. et al. Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons. Proc. Natl Acad. Sci. USA 104, 15917–15922 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  310. McIntyre, J. C. et al. Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model. Nat. Med. 18, 1423–1428 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  311. Kaneko-Goto, T. et al. Goofy coordinates the acuity of olfactory signaling. J. Neurosci. 33, 12987–12996 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  312. Mulvaney, B. D. & Heist, H. E. Centriole migration during regeneration and normal development of olfactory epithelium. J. Ultrastruct. Res. 35, 274–281 (1971).

    Article  CAS  PubMed  Google Scholar 

  313. Menco, B. P. & Farbman, A. I. Genesis of cilia and microvilli of rat nasal epithelia during pre-natal development. I. Olfactory epithelium, qualitative studies. J. Cell Sci. 78, 283–310 (1985).

    CAS  PubMed  Google Scholar 

  314. Cuschieri, A. & Bannister, L. H. The development of the olfactory mucosa in the mouse: electron microscopy. J. Anat. 119, 471–498 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Research in the Spassky laboratory was financed by the Institut National pour la Santé Et la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), the Ecole Normale Supérieure (ENS), the Agence Nationale de la Recherche (ANR-12-BSV4-0006 and ANRJCJC-15-CE13-0005-01), the European Research Council (ERC Consolidator grant 647466), the Fondation pour la Recherche Médicale (FRM20140329547), the Cancéropôle Ile-de-France (2014-1-PL BIO-11-INSERM 12–1) and the Fondation Pierre-Gilles de Gennes (FPGG03). The authors are grateful to the members of their laboratory for insightful and stimulating discussions.

Author information

Authors and Affiliations

  1. École Normale Supérieure, PSL Research University, CNRS, Inserm, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Paris, F-75005, France

    Nathalie Spassky & Alice Meunier

Authors
  1. Nathalie Spassky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alice Meunier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Nathalie Spassky or Alice Meunier.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Apical plasma membrane

In epithelial cells, the membrane located towards the lumen in a body tube or cavity.

Rotational polarity

The orientation of ciliary beating.

Translational polarity

Planar asymmetric localization of clusters of basal bodies on the apical area of multiciliated cells.

Ventricle epithelia

Single layers of cells lining the surface of the brain ventricles.

Secretory cells

Non-ciliated cells that secrete mucus into the respiratory tract, or fluids rich in nutrients into the reproductive tracts.

Basal cell

Undifferentiated airway cells localized deep in the respiratory epithelium and characterized by the expression of p63 and SOX2.

Coiled-coil domain

α-Helix-containing structural domain in proteins that are coiled together to form dimers or trimers.

Procentriole

Immature centriole or basal body in the process of growth.

Morphants

Organisms treated with a morpholino oligomer to decrease gene expression.

Distal appendages

Accessory components of mature centrioles that are involved in centriole docking at the vesicular or apical plasma membrane.

Secretory vesicles

Cytoplasmic vesicles that fuse with the apical surface of the cell.

Exocyst

A multiple-subunit complex that is required for the interaction of secretory vesicles with the plasma membrane, in preparation for membrane fusion.

Transition zone

The most proximal region of a cilium, upstream of the distal appendages of the basal body.

Microtubule organizing centre

Major site of microtubule nucleation and anchoring in a cell.

Basal-foot caps

Slight swellings at the ends of basal foot conical structures.

Myosin Id

A short-tailed class I myosin; a monomeric actin-based motor.

Metachronal

Self-organization of ciliary beating in a wave-like pattern.

Glycocalyx

The polysaccharide matrix that surrounds the cell membrane.

Sperm capacitation

Physiological changes of spermatozoa that give them the ability to penetrate and fertilize an egg.

Interstitial fluids

Extracellular fluids formed from plasma at the capillary walls in the brain.

Near-wall CSF circulation

Movement of cerebrospinal fluid (CSF) close to the ventricular walls that is opposed to the movement of CSF in the central region of the cavity.

Basal process

Cell extension from the cell body that contacts the pial surface of the brain.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Spassky, N., Meunier, A. The development and functions of multiciliated epithelia. Nat Rev Mol Cell Biol 18, 423–436 (2017). https://doi.org/10.1038/nrm.2017.21

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2017.21

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing