Molecular Neurobiology

, Volume 45, Issue 3, pp 564–570 | Cite as

Basic Biology and Mechanisms of Neural Ciliogenesis and the B9 Family

Article

Abstract

Although the discovery of cilia is one of the earliest in cell biology, the past two decades have witnessed an explosion of new insight into these enigmatic organelles. While long believed to be vestigial, cilia have recently moved into the spotlight as key players in multiple cellular processes, including brain development and homeostasis. This review focuses on the rapidly expanding basic biology of neural cilia, with special emphasis on the newly emerging B9 family of proteins. In particular, recent findings have identified a critical role for the B9 complex in a network of protein interactions that take place at the ciliary transition zone (TZ). We describe the essential role of these protein complexes in signaling cascades that require primary (nonmotile) cilia, including the sonic hedgehog pathway. Loss or dysfunction of ciliary trafficking and TZ function are linked to a number of neurologic diseases, which we propose to classify as neural ciliopathies. When taken together, the studies reviewed herein point to critical roles played by neural cilia, both in normal physiology and in disease.

Keywords

Primary cilia Neural ciliogenesis Neural ciliopathy B9-C2 family Ciliary signaling Stem cell Progenitor 

References

  1. 1.
    Dobell C, van Leeuwenhoek A (1958) Antony van Leeuwenhoek and his “Little animals”: being some account of the father of protozoology and bacteriology and his multifarious discoveries in these disciplines. Russell & Russell, New YorkGoogle Scholar
  2. 2.
    Haimo LT, Rosenbaum JL (1981) Cilia, flagella, and microtubules. J Cell Biol 91(3 Pt 2):125s–130sPubMedCrossRefGoogle Scholar
  3. 3.
    Satir P (1995) Landmarks in cilia research from Leeuwenhoek to us. Cell Motil Cytoskeleton 32(2):90–94PubMedCrossRefGoogle Scholar
  4. 4.
    Zimmerman KW (1898) Beitrage zur kenntniss einiger drusen und epithelien. Archiv for Mikrosk Anat 52:552–706CrossRefGoogle Scholar
  5. 5.
    Dellinger OP (1909) The cilium as a key to the structure of contractile protoplasm. J Morphol 20:171–209CrossRefGoogle Scholar
  6. 6.
    Grave C, Schmitt FO (1924) A Mechanism for the coordination and regulation of the movement of cilia of epithelia. Science 60(1550):246–248PubMedCrossRefGoogle Scholar
  7. 7.
    Jakus MA, Hall CE (1946) Electron microscope observations of the trichocysts and cilia of Paramecium. Biol Bull 91(02):141–144PubMedCrossRefGoogle Scholar
  8. 8.
    Dahl HA (1963) Fine structure of cilia in rat cerebral cortex. Z Zellforsch Mikrosk Anat 60:369–386PubMedCrossRefGoogle Scholar
  9. 9.
    Karlsson U (1966) Three-dimensional studies of neurons in the lateral geniculate nucleus of the rat. I. Organelle organization in the perikaryon and its proximal branches. J Ultrastruct Res 16(5):429–481PubMedCrossRefGoogle Scholar
  10. 10.
    Louvi A, Grove EA (2011) Cilia in the CNS: the quiet organelle claims center stage. Neuron 69(6):1046–1060PubMedCrossRefGoogle Scholar
  11. 11.
    Kozminski KG, Johnson KA et al (1993) A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc Natl Acad Sci USA 90(12):5519–5523PubMedCrossRefGoogle Scholar
  12. 12.
    Kozminski KG, Beech PL et al (1995) The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane. J Cell Biol 131(6 Pt 1):1517–1527PubMedCrossRefGoogle Scholar
  13. 13.
    Perkins LA, Hedgecock EM et al (1986) Mutant sensory cilia in the nematode Caenorhabditis elegans. Dev Biol 117(2):456–487PubMedCrossRefGoogle Scholar
  14. 14.
    Cole DG, Diener DR et al (1998) Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J Cell Biol 141(4):993–1008PubMedCrossRefGoogle Scholar
  15. 15.
    Collet J, Spike CA et al (1998) Analysis of osm-6, a gene that affects sensory cilium structure and sensory neuron function in Caenorhabditis elegans. Genetics 148(1):187–200PubMedGoogle Scholar
  16. 16.
    Signor D, Wedaman KP et al (1999) Role of a class DHC1b dynein in retrograde transport of IFT motors and IFT raft particles along cilia, but not dendrites, in chemosensory neurons of living Caenorhabditis elegans. J Cell Biol 147(3):519–530PubMedCrossRefGoogle Scholar
  17. 17.
    Rosenbaum JL, Witman GB (2002) Intraflagellar transport. Nat Rev Mol Cell Biol 3(11):813–825PubMedCrossRefGoogle Scholar
  18. 18.
    Pazour GJ, Dickert BL et al (2000) Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol 151(3):709–718PubMedCrossRefGoogle Scholar
  19. 19.
    Rohatgi R, Milenkovic L et al (2007) Patched1 regulates hedgehog signaling at the primary cilium. Science 317(5836):372–376PubMedCrossRefGoogle Scholar
  20. 20.
    Milenkovic L, Scott MP et al (2009) Lateral transport of smoothened from the plasma membrane to the membrane of the cilium. J Cell Biol 187(3):365–374PubMedCrossRefGoogle Scholar
  21. 21.
    Huangfu D, Liu A et al (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426(6962):83–87PubMedCrossRefGoogle Scholar
  22. 22.
    Huangfu D, Anderson KV (2005) Cilia and hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA 102(32):11325–11330PubMedCrossRefGoogle Scholar
  23. 23.
    May SR, Ashique AM et al (2005) Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol 287(2):378–389PubMedCrossRefGoogle Scholar
  24. 24.
    Tuson M, He M et al (2011) Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development 138(22):4921–4930PubMedCrossRefGoogle Scholar
  25. 25.
    Delattre M, Briand S et al (1999) The suppressor of fused gene, involved in Hedgehog signal transduction in Drosophila, is conserved in mammals. Dev Genes Evol 209(5):294–300PubMedCrossRefGoogle Scholar
  26. 26.
    Ding Q, Fukami S et al (1999) Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli1. Curr Biol 9(19):1119–1122PubMedCrossRefGoogle Scholar
  27. 27.
    Kogerman P, Grimm T et al (1999) Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol 1(5):312–319PubMedCrossRefGoogle Scholar
  28. 28.
    Pearse RV 2nd, Collier LS et al (1999) Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators. Dev Biol 212(2):323–336PubMedCrossRefGoogle Scholar
  29. 29.
    Stone DM, Murone M et al (1999) Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli. J Cell Sci 112(Pt 23):4437–4448PubMedGoogle Scholar
  30. 30.
    Cooper AF, Yu KP et al (2005) Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development 132(19):4407–4417PubMedCrossRefGoogle Scholar
  31. 31.
    Svard J, Heby-Henricson K et al (2006) Genetic elimination of suppressor of fused reveals an essential repressor function in the mammalian hedgehog signaling pathway. Dev Cell 10(2):187–197PubMedCrossRefGoogle Scholar
  32. 32.
    Jia J, Kolterud A et al (2009) Suppressor of fused inhibits mammalian hedgehog signaling in the absence of cilia. Dev Biol 330(2):452–460PubMedCrossRefGoogle Scholar
  33. 33.
    Haycraft CJ, Banizs B et al (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1(4):e53PubMedCrossRefGoogle Scholar
  34. 34.
    Tukachinsky H, Lopez LV et al (2010) A mechanism for vertebrate hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J Cell Biol 191(2):415–428PubMedCrossRefGoogle Scholar
  35. 35.
    Zeng H, Jia J et al (2010) Coordinated translocation of mammalian Gli proteins and suppressor of fused to the primary cilium. PLoS One 5(12):e15900PubMedCrossRefGoogle Scholar
  36. 36.
    Chen MH, Wilson CW et al (2009) Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev 23(16):1910–1928PubMedCrossRefGoogle Scholar
  37. 37.
    Humke EW, Dorn KV et al (2010) The output of hedgehog signaling is controlled by the dynamic association between suppressor of fused and the Gli proteins. Genes Dev 24(7):670–682PubMedCrossRefGoogle Scholar
  38. 38.
    Hu Q, Milenkovic L et al (2010) A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution. Science 329(5990):436–439PubMedCrossRefGoogle Scholar
  39. 39.
    Seeley ES, Nachury MV (2010) The perennial organelle: assembly and disassembly of the primary cilium. J Cell Sci 123(Pt 4):511–518PubMedCrossRefGoogle Scholar
  40. 40.
    Hu Q, Nelson WJ (2011) Ciliary diffusion barrier: the gatekeeper for the primary cilium compartment. Cytoskeleton (Hoboken) 68(6):313–324Google Scholar
  41. 41.
    Town T, Breunig JJ et al (2008) The stumpy gene is required for mammalian ciliogenesis. Proc Natl Acad Sci USA 105(8):2853–2858PubMedCrossRefGoogle Scholar
  42. 42.
    Garcia-Gonzalo FR, Corbit KC et al (2011) A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet 43(8):776–784PubMedCrossRefGoogle Scholar
  43. 43.
    Williams CL, Li C et al (2011) MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol 192(6):1023–1041PubMedCrossRefGoogle Scholar
  44. 44.
    Chih B, Liu P et al (2012) A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol 14(1):61–72CrossRefGoogle Scholar
  45. 45.
    Zhang D, Aravind L (2010) Identification of novel families and classification of the C2 domain superfamily elucidate the origin and evolution of membrane targeting activities in eukaryotes. Gene 469(1–2):18–30PubMedCrossRefGoogle Scholar
  46. 46.
    Williams CL, Winkelbauer ME et al (2008) Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis. Mol Biol Cell 19(5):2154–2168PubMedCrossRefGoogle Scholar
  47. 47.
    Dowdle WE, Robinson JF et al (2011) Disruption of a ciliary B9 protein complex causes Meckel syndrome. Am J Hum Genet 89(1):94–110PubMedCrossRefGoogle Scholar
  48. 48.
    Breunig JJ, Sarkisian MR et al (2008) Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc Natl Acad Sci USA 105(35):13127–13132PubMedCrossRefGoogle Scholar
  49. 49.
    Chizhikov VV, Davenport J et al (2007) Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. J Neurosci 27(36):9780–9789PubMedCrossRefGoogle Scholar
  50. 50.
    Spassky N, Han YG et al (2008) Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool. Dev Biol 317(1):246–259PubMedCrossRefGoogle Scholar
  51. 51.
    Gherman A, Davis EE et al (2006) The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat Genet 38(9):961–962PubMedCrossRefGoogle Scholar
  52. 52.
    Kyttala M, Tallila J et al (2006) MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nat Genet 38(2):155–157PubMedCrossRefGoogle Scholar
  53. 53.
    Weatherbee SD, Niswander LA et al (2009) A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and hedgehog signaling. Hum Mol Genet 18(23):4565–4575PubMedCrossRefGoogle Scholar
  54. 54.
    Breunig JJ, Haydar TF et al (2011) Neural stem cells: historical perspective and future prospects. Neuron 70(4):614–625PubMedCrossRefGoogle Scholar
  55. 55.
    Guillemot F (2007) Cell fate specification in the mammalian telencephalon. Prog Neurobiol 83(1):37–52PubMedCrossRefGoogle Scholar
  56. 56.
    Han YG, Spassky N et al (2008) Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci 11(3):277–284PubMedCrossRefGoogle Scholar
  57. 57.
    Altman J, Bayer SA (1990) Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J Comp Neurol 301(3):365–381PubMedCrossRefGoogle Scholar
  58. 58.
    Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250PubMedCrossRefGoogle Scholar
  59. 59.
    Kumamoto N, Gu Y et al (2012) A role for primary cilia in glutamatergic synaptic integration of adult-born neurons. Nat Neurosci 15:399–405Google Scholar
  60. 60.
    Badano JL, Mitsuma N et al (2006) The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7:125–148PubMedCrossRefGoogle Scholar
  61. 61.
    Adams M, Smith UM et al (2008) Recent advances in the molecular pathology, cell biology and genetics of ciliopathies. J Med Genet 45(5):257–267PubMedCrossRefGoogle Scholar
  62. 62.
    Gerdes JM, Davis EE et al (2009) The vertebrate primary cilium in development, homeostasis, and disease. Cell 137(1):32–45PubMedCrossRefGoogle Scholar
  63. 63.
    Fliegauf M, Benzing T et al (2007) When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 8(11):880–893PubMedCrossRefGoogle Scholar
  64. 64.
    Budny B, Chen W et al (2006) A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet 120(2):171–178PubMedCrossRefGoogle Scholar
  65. 65.
    Martinez-Campos M, Basto R et al (2004) The Drosophila pericentrin-like protein is essential for cilia/flagella function, but appears to be dispensable for mitosis. J Cell Biol 165(5):673–683PubMedCrossRefGoogle Scholar
  66. 66.
    Rauch A, Thiel CT et al (2008) Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science 319(5864):816–819PubMedCrossRefGoogle Scholar
  67. 67.
    Bishop GA, Berbari NF et al (2007) Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. J Comp Neurol 505(5):562–571PubMedCrossRefGoogle Scholar
  68. 68.
    Arellano JI, Guadiana SM et al (2012) Development and distribution of neuronal cilia in mouse neocortex. J Comp Neurol 520(4):848–873PubMedCrossRefGoogle Scholar
  69. 69.
    Wallace FM (2008) Chapter 1 basal bodies: platforms for building cilia. In: Bradley KY (ed) Current topics in developmental biology, vol 85. Academic, Burlington, pp 1–22Google Scholar
  70. 70.
    Pan J, Snell W (2007) The primary cilium: keeper of the key to cell division. Cell 129(7):1255–1257PubMedCrossRefGoogle Scholar
  71. 71.
    Wang X, Tsai JW et al (2009) Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature 461(7266):947–955PubMedCrossRefGoogle Scholar
  72. 72.
    Han YG, Kim HJ et al (2009) Dual and opposing roles of primary cilia in medulloblastoma development. Nat Med 15(9):1062–1065PubMedCrossRefGoogle Scholar
  73. 73.
    Pietsch T, Waha A et al (1997) Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57(11):2085–2088PubMedGoogle Scholar
  74. 74.
    Raffel C, Jenkins RB et al (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57(5):842–845PubMedGoogle Scholar
  75. 75.
    Gilbertson RJ, Ellison DW (2008) The origins of medulloblastoma subtypes. Annu Rev Pathol 3:341–365PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Biomedical Sciences and Regenerative Medicine InstituteCedars-Sinai Medical CenterLos AngelesUSA
  2. 2.Department of Neurosurgery and Maxine Dunitz Neurosurgical InstituteCedars-Sinai Medical CenterLos AngelesUSA
  3. 3.Department of Medicine, David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA
  4. 4.Regenerative Medicine InstituteCedars-Sinai Medical CenterLos AngelesUSA

Personalised recommendations