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PMID: 20544253 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Neuronal ciliary signaling in homeostasis and disease.

Cellular and molecular life sciences : CMLS ·Vol. 67 ·No. 19 ·2010-10-00 ·Pages 3287-97

Green JA, Mykytyn K

Abstract

Primary cilia are a class of cilia that are typically solitary, immotile appendages present on nearly every mammalian cell type. Primary cilia are believed to perform specialized sensory and signaling functions that are important for normal development and cellular homeostasis. Indeed, primary cilia dysfunction is now linked to numerous human diseases and genetic disorders. Collectively, primary cilia disorders are termed as ciliopathies and present with a wide range of clinical features, including cystic kidney disease, retinal degeneration, obesity, polydactyly, anosmia, intellectual disability, and brain malformations. Although significant progress has been made in elucidating the functions of primary cilia on some cell types, the precise functions of most primary cilia remain unknown. This is particularly true for primary cilia on neurons throughout the mammalian brain. This review will introduce primary cilia and ciliary signaling pathways with a focus on neuronal cilia and their putative functions and roles in human diseases.

MeSH Terms
Cilia/metabolism,physiology Genetic Diseases, Inborn/metabolism Homeostasis Humans Kidney Diseases, Cystic/metabolism Neurons/cytology,physiology Polycystic Kidney Diseases/metabolism Polydactyly/metabolism Retinal Degeneration/metabolism Signal Transduction
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Green Jill A
Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Mykytyn Kirk
References (104)
104 references, click to expand
  1. The neuronal primary cilium--an extrasynaptic signaling device.
    Cell Signal. 2004 Jul;16(7):763-7 PMID: 15115655
  2. Non-random distribution and sensory functions of primary cilia in vascular smooth muscle cells.
    Kidney Blood Press Res. 2008;31(3):171-84 PMID: 18483460
  3. Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance.
    J Clin Invest. 2001 Feb;107(3):379-86 PMID: 11160162
  4. When cilia go bad: cilia defects and ciliopathies.
    Nat Rev Mol Cell Biol. 2007 Nov;8(11):880-93 PMID: 17955020
  5. Identification of ciliary localization sequences within the third intracellular loop of G protein-coupled receptors.
    Mol Biol Cell. 2008 Apr;19(4):1540-7 PMID: 18256283
  6. Hippocampal neurons possess primary cilia in culture.
    J Neurosci Res. 2007 Apr;85(5):1095-100 PMID: 17304575
  7. The retinal ciliopathies.
    Ophthalmic Genet. 2007 Sep;28(3):113-25 PMID: 17896309
  8. Mice lacking melanin-concentrating hormone are hypophagic and lean.
    Nature. 1998 Dec 17;396(6712):670-4 PMID: 9872314
  9. Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors.
    Neuropsychopharmacology. 1999 Aug;21(2 Suppl):68S-76S PMID: 10432491
  10. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease.
    Curr Biol. 2007 Sep 18;17(18):1586-94 PMID: 17825558
  11. Multiple primary cilia modulate the fluid transcytosis in choroid plexus epithelium.
    Traffic. 2010 Feb;11(2):287-301 PMID: 19958467
  12. Regulation and function of somatostatin receptors.
    J Neurochem. 2004 Jun;89(5):1057-91 PMID: 15147500
  13. The electrochemical basis of odor transduction in vertebrate olfactory cilia.
    Chem Senses. 2008 Nov;33(9):839-59 PMID: 18703537
  14. Localization of five somatostatin receptors in the rat central nervous system using subtype-specific antibodies.
    J Physiol Paris. 2000 May-Aug;94(3-4):259-64 PMID: 11088003
  15. The primary cilium as a complex signaling center.
    Curr Biol. 2009 Jul 14;19(13):R526-35 PMID: 19602418
  16. Olfactory cilia: linking sensory cilia function and human disease.
    Chem Senses. 2009 Jun;34(5):451-64 PMID: 19406873
  17. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.
    Nat Genet. 2003 Feb;33(2):129-37 PMID: 12514735
  18. Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling.
    Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13127-32 PMID: 18728187
  19. Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation.
    J Neurosci. 2007 Apr 11;27(15):4201-9 PMID: 17428998
  20. The fine structure of secretory neurons in the preoptic nucleus of the goldish (Carassius auratus).
    Anat Rec. 1960 Dec;138:417-43 PMID: 13732184
  21. Adult type 3 adenylyl cyclase-deficient mice are obese.
    PLoS One. 2009 Sep 11;4(9):e6979 PMID: 19750222
  22. Clinical evidence of decreased olfaction in Bardet-Biedl syndrome caused by a deletion in the BBS4 gene.
    Am J Med Genet A. 2005 Feb 1;132A(4):343-6 PMID: 15654695
  23. The primary cilium at the crossroads of mammalian hedgehog signaling.
    Curr Top Dev Biol. 2008;85:225-60 PMID: 19147008
  24. Cilia and developmental signaling.
    Annu Rev Cell Dev Biol. 2007;23:345-73 PMID: 17506691
  25. Vasopressin receptor-mediated functional signaling pathway in primary cilia of renal epithelial cells.
    Am J Physiol Renal Physiol. 2009 Jan;296(1):F87-97 PMID: 18945824
  26. Development and disease of the photoreceptor cilium.
    Clin Genet. 2009 Aug;76(2):137-45 PMID: 19790290
  27. Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders.
    Pharmacol Ther. 2008 Feb;117(2):207-31 PMID: 18068807
  28. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling.
    Curr Top Dev Biol. 2008;85:23-61 PMID: 19147001
  29. Embryonic expression of pericentrin suggests universal roles in ciliogenesis.
    Dev Genes Evol. 2006 Sep;216(9):537-42 PMID: 16534625
  30. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia.
    Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4242-6 PMID: 18334641
  31. The neuronal primary cilium: driver of neurogenesis and memory formation in the hippocampal dentate gyrus?
    Cell Signal. 2009 Sep;21(9):1351-5 PMID: 19249355
  32. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist.
    Nat Med. 2002 Aug;8(8):825-30 PMID: 12118247
  33. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells.
    Nat Neurosci. 2008 Mar;11(3):277-84 PMID: 18297065
  34. Intraflagellar transport.
    Nat Rev Mol Cell Biol. 2002 Nov;3(11):813-25 PMID: 12415299
  35. Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase.
    Am J Physiol Renal Physiol. 2000 Sep;279(3):F400-16 PMID: 10966920
  36. Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats.
    Br J Pharmacol. 2006 Aug;148(7):973-83 PMID: 16783408
  37. Motile cilia of human airway epithelia are chemosensory.
    Science. 2009 Aug 28;325(5944):1131-4 PMID: 19628819
  38. 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. 2005 Nov 15;287(2):378-89 PMID: 16229832
  39. Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1.
    Circulation. 2008 Mar 4;117(9):1161-71 PMID: 18285569
  40. Olfactory cilia: our direct neuronal connection to the external world.
    Curr Top Dev Biol. 2008;85:333-70 PMID: 19147011
  41. Intraflagellar transport.
    Annu Rev Cell Dev Biol. 2003;19:423-43 PMID: 14570576
  42. Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool.
    Dev Biol. 2008 May 1;317(1):246-59 PMID: 18353302
  43. The proteome of the mouse photoreceptor sensory cilium complex.
    Mol Cell Proteomics. 2007 Aug;6(8):1299-317 PMID: 17494944
  44. Rhodopsin transport in the membrane of the connecting cilium of mammalian photoreceptor cells.
    Cell Motil Cytoskeleton. 2000 Jun;46(2):95-107 PMID: 10891855
  45. Polaris, a protein disrupted in orpk mutant mice, is required for assembly of renal cilium.
    Am J Physiol Renal Physiol. 2002 Mar;282(3):F541-52 PMID: 11832437
  46. NDP kinase moves into developing primary cilia.
    Cell Motil Cytoskeleton. 2004 Sep;59(1):62-73 PMID: 15259056
  47. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist.
    Nat Med. 2003 Oct;9(10):1323-6 PMID: 14502283
  48. Somatostatin and its receptor family.
    Front Neuroendocrinol. 1999 Jul;20(3):157-98 PMID: 10433861
  49. Isolation and characterization of cholangiocyte primary cilia.
    Am J Physiol Gastrointest Liver Physiol. 2006 Sep;291(3):G500-9 PMID: 16899714
  50. The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance.
    J Cell Biol. 2002 Apr 1;157(1):103-13 PMID: 11916979
  51. Loss of primary cilia results in deregulated and unabated apical calcium entry in ARPKD collecting duct cells.
    Am J Physiol Renal Physiol. 2006 Jun;290(6):F1320-8 PMID: 16396941
  52. The renal cell primary cilium functions as a flow sensor.
    Curr Opin Nephrol Hypertens. 2003 Sep;12(5):517-20 PMID: 12920399
  53. Role of primary cilia in brain development and cancer.
    Curr Opin Neurobiol. 2010 Feb;20(1):58-67 PMID: 20080044
  54. Cilia and Hedgehog responsiveness in the mouse.
    Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11325-30 PMID: 16061793
  55. Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain.
    J Comp Neurol. 2007 Dec 10;505(5):562-71 PMID: 17924533
  56. Mechanoregulation of intracellular Ca2+ concentration is attenuated in collecting duct of monocilium-impaired orpk mice.
    Am J Physiol Renal Physiol. 2005 Nov;289(5):F978-88 PMID: 15972389
  57. Somatostatinergic systems in brain: networks and functions.
    Mol Cell Endocrinol. 2008 May 14;286(1-2):75-87 PMID: 17997029
  58. Localization of extracellular matrix receptors on the chondrocyte primary cilium.
    J Histochem Cytochem. 2006 Sep;54(9):1005-14 PMID: 16651393
  59. Localization of 5-HT(6) receptors at the plasma membrane of neuronal cilia in the rat brain.
    Brain Res. 2000 Jul 28;872(1-2):271-5 PMID: 10924708
  60. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein.
    Cell. 1998 Dec 11;95(6):829-37 PMID: 9865700
  61. Neuronal primary cilia: a review.
    Cell Biol Int. 2004;28(2):111-8 PMID: 14984756
  62. Identification of G protein-coupled receptor genes from the human genome sequence.
    FEBS Lett. 2002 Jun 5;520(1-3):97-101 PMID: 12044878
  63. Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors.
    Cell. 2000 Jul 21;102(2):175-87 PMID: 10943838
  64. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function.
    PLoS Genet. 2005 Oct;1(4):e53 PMID: 16254602
  65. Cilium-generated signaling and cilia-related disorders.
    Lab Invest. 2005 Apr;85(4):452-63 PMID: 15723088
  66. Bending the MDCK cell primary cilium increases intracellular calcium.
    J Membr Biol. 2001 Nov 1;184(1):71-9 PMID: 11687880
  67. Identification of a specialized adenylyl cyclase that may mediate odorant detection.
    Science. 1990 Dec 7;250(4986):1403-6 PMID: 2255909
  68. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease.
    Nat Med. 2004 Apr;10(4):363-4 PMID: 14991049
  69. Somatostatin and somatostatin receptor physiology.
    Endocrine. 2003 Apr;20(3):255-64 PMID: 12721505
  70. Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity.
    Endocrinology. 2002 Jul;143(7):2469-77 PMID: 12072376
  71. Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse.
    Nat Genet. 2004 Sep;36(9):994-8 PMID: 15322545
  72. Patched1 regulates hedgehog signaling at the primary cilium.
    Science. 2007 Jul 20;317(5836):372-6 PMID: 17641202
  73. Vertebrate Smoothened functions at the primary cilium.
    Nature. 2005 Oct 13;437(7061):1018-21 PMID: 16136078
  74. Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice.
    Neuron. 2000 Sep;27(3):487-97 PMID: 11055432
  75. Localization of intraflagellar transport protein IFT52 identifies basal body transitional fibers as the docking site for IFT particles.
    Curr Biol. 2001 Oct 16;11(20):1586-90 PMID: 11676918
  76. Fine structure of cilia in rat cerebral cortex.
    Z Zellforsch Mikrosk Anat. 1963;60:369-86 PMID: 14024614
  77. Hedgehog signalling in the mouse requires intraflagellar transport proteins.
    Nature. 2003 Nov 6;426(6962):83-7 PMID: 14603322
  78. Primary cilia of human endothelial cells disassemble under laminar shear stress.
    J Cell Biol. 2004 Mar 15;164(6):811-7 PMID: 15024030
  79. 5-ht6 receptors.
    Curr Drug Targets CNS Neurol Disord. 2004 Feb;3(1):59-79 PMID: 14965245
  80. Characterization of single channel currents from primary cilia of renal epithelial cells.
    J Biol Chem. 2005 Oct 14;280(41):34718-22 PMID: 16079132
  81. The vertebrate primary cilium in development, homeostasis, and disease.
    Cell. 2009 Apr 3;137(1):32-45 PMID: 19345185
  82. Ciliary dysfunction in developmental abnormalities and diseases.
    Curr Top Dev Biol. 2008;85:371-427 PMID: 19147012
  83. Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool.
    J Neurosci. 2007 Sep 5;27(36):9780-9 PMID: 17804638
  84. 5-HT6 receptors: a novel target for cognitive enhancement.
    Pharmacol Ther. 2005 Dec;108(3):320-33 PMID: 16005519
  85. Sensory reception is an attribute of both primary cilia and motile cilia.
    J Cell Sci. 2010 Feb 15;123(Pt 4):505-9 PMID: 20144998
  86. The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination.
    Development. 2000 Jun;127(11):2347-55 PMID: 10804177
  87. A role for melanin-concentrating hormone in the central regulation of feeding behaviour.
    Nature. 1996 Mar 21;380(6571):243-7 PMID: 8637571
  88. Somatostatin signaling in neuronal cilia is critical for object recognition memory.
    J Neurosci. 2010 Mar 24;30(12):4306-14 PMID: 20335466
  89. Sensory cilia and integration of signal transduction in human health and disease.
    Traffic. 2007 Feb;8(2):97-109 PMID: 17241444
  90. Hedgehog signaling in animal development: paradigms and principles.
    Genes Dev. 2001 Dec 1;15(23):3059-87 PMID: 11731473
  91. Cyclic nucleotide signaling in polycystic kidney disease.
    Kidney Int. 2010 Jan;77(2):129-40 PMID: 19924104
  92. 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 U S A. 2007 Oct 2;104(40):15917-22 PMID: 17898177
  93. Two populations of node monocilia initiate left-right asymmetry in the mouse.
    Cell. 2003 Jul 11;114(1):61-73 PMID: 12859898
  94. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors.
    Development. 2005 Jul;132(13):3103-11 PMID: 15930098
  95. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella.
    J Cell Biol. 2000 Oct 30;151(3):709-18 PMID: 11062270
  96. Developmental changes in frequency of the ciliary somatostatin receptor 3 protein.
    Brain Res. 2009 Jan 16;1249:101-12 PMID: 18992731
  97. Targeting proteins to the ciliary membrane.
    Curr Top Dev Biol. 2008;85:115-49 PMID: 19147004
  98. Transmembrane currents in frog olfactory cilia.
    J Membr Biol. 1991 Feb;120(1):75-81 PMID: 1850487
  99. The ultrastructure of the innersegments of the retinal rods of the guinea pig eye as revealed by electron microscopy.
    J Cell Comp Physiol. 1953 Aug;42(1):45-70 PMID: 13084706
  100. Selective targeting of somatostatin receptor 3 to neuronal cilia.
    Neuroscience. 1999 Mar;89(3):909-26 PMID: 10199624
  101. The proteome of rat olfactory sensory cilia.
    Proteomics. 2009 Jan;9(2):322-34 PMID: 19086097
  102. Developmental roles and clinical significance of hedgehog signaling.
    Curr Top Dev Biol. 2003;53:1-114 PMID: 12509125
  103. Olfactory perception: receptors, cells, and circuits.
    Cell. 2009 Oct 2;139(1):45-59 PMID: 19804753
  104. Cholangiocyte cilia detect changes in luminal fluid flow and transmit them into intracellular Ca2+ and cAMP signaling.
    Gastroenterology. 2006 Sep;131(3):911-20 PMID: 16952559
Article Info
Journal
Cellular and molecular life sciences : CMLS
Abbr.
Cell Mol Life Sci
ISSN
1420-9071
Published
2010-10-00
Epub
2010-00-11
Pages
3287-97
Language
English
Region
Switzerland
NLM ID
9705402
PMCID
PMC3349968
Subset
IM
Grants
NIGMS NIH HHS · R01 GM083120 · United States
NIGMS NIH HHS · T32 GM068412 · United States
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