Functional Study of the Primary Cilia in ADPKD

  • Je Yeong KoEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 933)


The primary cilium is a microtubule-based organelle that is considered to be a cellular antennae, because proteins related to multiple signaling pathways such as Wnt, PDGFRα, Hh, and mechanosignaling are localized to the membrane of the primary cilium. In the kidney, primary cilia extend from the cell membrane to the lumen of renal tubules to respond to fluidic stress. Recent studies have indicated that the disruption of ciliary proteins including polycystin-1 (PC1), polycystin-2 (PC2), and members of the intraflagellar transport (IFT) family induce the development of polycystic kidney disease (PKD), suggesting that the malformation or absence of primary cilia is a driving force of the onset of PKD. Therefore, in this chapter, the renal cystogenesis mechanism induced by cilia defects and pathogenic ciliary proteins associated with PKD development will be described.


Cilia Ciliogenesis Cystogenesis Intraflagellar transport 


  1. Avasthi P, Marshall WF (2012) Stages of ciliogenesis and regulation of ciliary length. Differ Res Biolog Diver 83(2):S30–S42. doi: 10.1016/j.diff.2011.11.015 CrossRefGoogle Scholar
  2. Basten SG, Giles RH (2013) Functional aspects of primary cilia in signaling, cell cycle and tumorigenesis. Cilia 2(1):6. doi: 10.1186/2046-2530-2-6 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bastos AP, Onuchic LF (2011) Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease. Braz J Med Biol Res = Revista brasileira de pesquisas medicas e biologicas/Sociedade Brasileira de Biofisica [et al] 44(7):606–617Google Scholar
  4. Boehlke C, Kotsis F, Patel V, Braeg S, Voelker H, Bredt S, Beyer T, Janusch H, Hamann C, Godel M, Muller K, Herbst M, Hornung M, Doerken M, Kottgen M, Nitschke R, Igarashi P, Walz G, Kuehn EW (2010) Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat Cell Biol 12(11):1115–1122. doi: 10.1038/ncb2117 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Boehlke C, Janusch H, Hamann C, Powelske C, Mergen M, Herbst H, Kotsis F, Nitschke R, Kuehn EW (2015) A cilia independent role of Ift88/polaris during cell migration. PLoS One 10(10):e0140378. doi: 10.1371/journal.pone.0140378 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chapin HC, Caplan MJ (2010) The cell biology of polycystic kidney disease. J Cell Biol 191(4):701–710. doi: 10.1083/jcb.201006173 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chaya T, Omori Y, Kuwahara R, Furukawa T (2014) ICK is essential for cell type-specific ciliogenesis and the regulation of ciliary transport. EMBO J 33(11):1227–1242. doi: 10.1002/embj.201488175 PubMedPubMedCentralGoogle Scholar
  8. Christensen ST, Ott CM (2007) Cell signaling. A ciliary signaling switch. Science 317(5836):330–331. doi: 10.1126/science.1146180 CrossRefPubMedGoogle Scholar
  9. Cole DG, Diener DR, Himelblau AL, Beech PL, Fuster JC, Rosenbaum JL (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):993–1008CrossRefPubMedPubMedCentralGoogle Scholar
  10. Deane JA, Cole DG, Seeley ES, Diener DR, Rosenbaum JL (2001) Localization of intraflagellar transport protein IFT52 identifies basal body transitional fibers as the docking site for IFT particles. Curr Biol CB 11(20):1586–1590CrossRefPubMedGoogle Scholar
  11. Drummond IA (2012) Cilia functions in development. Curr Opin Cell Biol 24(1):24–30. doi: 10.1016/ CrossRefPubMedPubMedCentralGoogle Scholar
  12. Efimenko E, Blacque OE, Ou G, Haycraft CJ, Yoder BK, Scholey JM, Leroux MR, Swoboda P (2006) Caenorhabditis elegans DYF-2, an orthologue of human WDR19, is a component of the intraflagellar transport machinery in sensory cilia. Mol Biol Cell 17(11):4801–4811. doi: 10.1091/mbc.E06-04-0260 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Eguether T, San Agustin JT, Keady BT, Jonassen JA, Liang Y, Francis R, Tobita K, Johnson CA, Abdelhamed ZA, Lo CW, Pazour GJ (2014) IFT27 links the BBSome to IFT for maintenance of the ciliary signaling compartment. Dev Cell 31(3):279–290. doi: 10.1016/j.devcel.2014.09.011 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Follit JA, Tuft RA, Fogarty KE, Pazour GJ (2006) The intraflagellar transport protein IFT20 is associated with the Golgi complex and is required for cilia assembly. Mol Biol Cell 17(9):3781–3792. doi: 10.1091/mbc.E06-02-0133 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Goetz SC, Anderson KV (2010) The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11(5):331–344. doi: 10.1038/nrg2774 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Huang L, Lipschutz JH (2014) Cilia and polycystic kidney disease, kith and kin. Birth Defects Res C Embryo Today Rev 102(2):174–185. doi: 10.1002/bdrc.21066 CrossRefGoogle Scholar
  17. Ibanez-Tallon I, Heintz N, Omran H (2003) To beat or not to beat: roles of cilia in development and disease. Hum Mol Genet 12(Spec No 1):R27–R35CrossRefPubMedGoogle Scholar
  18. Ibraghimov-Beskrovnaya O, Natoli TA (2011) mTOR signaling in polycystic kidney disease. Trends Mol Med 17(11):625–633. doi: 10.1016/j.molmed.2011.06.003 CrossRefPubMedGoogle Scholar
  19. Ishikawa H, Marshall WF (2011) Ciliogenesis: building the cell’s antenna. Nat Rev Mol Cell Biol 12(4):222–234. doi: 10.1038/nrm3085 CrossRefPubMedGoogle Scholar
  20. Jin X, Mohieldin AM, Muntean BS, Green JA, Shah JV, Mykytyn K, Nauli SM (2014) Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli. Cell Mol Life Sci CMLS 71(11):2165–2178. doi: 10.1007/s00018-013-1483-1 CrossRefPubMedGoogle Scholar
  21. Jonassen JA, San Agustin J, Follit JA, Pazour GJ (2008) Deletion of IFT20 in the mouse kidney causes misorientation of the mitotic spindle and cystic kidney disease. J Cell Biol 183(3):377–384. doi: 10.1083/jcb.200808137 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Jonassen JA, SanAgustin J, Baker SP, Pazour GJ (2012) Disruption of IFT complex A causes cystic kidneys without mitotic spindle misorientation. J Am Soc Nephrol JASN 23(4):641–651. doi: 10.1681/ASN.2011080829 CrossRefPubMedGoogle Scholar
  23. Keady BT, Samtani R, Tobita K, Tsuchya M, San Agustin JT, Follit JA, Jonassen JA, Subramanian R, Lo CW, Pazour GJ (2012) IFT25 links the signal-dependent movement of Hedgehog components to intraflagellar transport. Dev Cell 22(5):940–951. doi: 10.1016/j.devcel.2012.04.009 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kobayashi T, Dynlacht BD (2011) Regulating the transition from centriole to basal body. J Cell Biol 193(3):435–444. doi: 10.1083/jcb.201101005 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122(Pt 20):3589–3594. doi: 10.1242/jcs.051011 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Lee JE, Gleeson JG (2011) A systems-biology approach to understanding the ciliopathy disorders. Genome Med 3(9):59. doi: 10.1186/gm275 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lee SH, Somlo S (2014) Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease. Kidney Res Clin Pract 33(2):73–78. doi: 10.1016/j.krcp.2014.05.002 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lehman JM, Michaud EJ, Schoeb TR, Aydin-Son Y, Miller M, Yoder BK (2008) The Oak Ridge Polycystic Kidney mouse: modeling ciliopathies of mice and men. Dev Dyn Off Publ Am Assoc Anat 237(8):1960–1971. doi: 10.1002/dvdy.21515 Google Scholar
  29. Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LS, Somlo S, Igarashi P (2003) Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci U S A 100(9):5286–5291. doi: 10.1073/pnas.0836980100 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Liu S, Lu W, Obara T, Kuida S, Lehoczky J, Dewar K, Drummond IA, Beier DR (2002) A defect in a novel Nek-family kinase causes cystic kidney disease in the mouse and in zebrafish. Development 129(24):5839–5846CrossRefPubMedGoogle Scholar
  31. Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S (2013) Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet 45(9):1004–1012. doi: 10.1038/ng.2715 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Mangolini A, de Stephanis L, Aguiari G (2016) Role of calcium in polycystic kidney disease: from signaling to pathology. World J Nephrol 5(1):76–83. doi: 10.5527/wjn.v5.i1.76 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Michaud EJ, Yoder BK (2006) The primary cilium in cell signaling and cancer. Cancer Res 66(13):6463–6467. doi: 10.1158/0008-5472.CAN-06-0462 CrossRefPubMedGoogle Scholar
  34. Moon H, Song J, Shin JO, Lee H, Kim HK, Eggenschwiller JT, Bok J, Ko HW (2014) Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling. Proc Natl Acad Sci U S A 111(23):8541–8546. doi: 10.1073/pnas.1323161111 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Mostov KE (2006) mTOR is out of control in polycystic kidney disease. Proc Natl Acad Sci U S A 103(14):5247–5248. doi: 10.1073/pnas.0601352103 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33(2):129–137. doi: 10.1038/ng1076 CrossRefPubMedGoogle Scholar
  37. Nauli SM, Rossetti S, Kolb RJ, Alenghat FJ, Consugar MB, Harris PC, Ingber DE, Loghman-Adham M, Zhou J (2006) Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. J Am Soc Nephrol JASN 17(4):1015–1025. doi: 10.1681/ASN.2005080830 CrossRefPubMedGoogle Scholar
  38. Nozawa YI, Lin C, Chuang PT (2013) Hedgehog signaling from the primary cilium to the nucleus: an emerging picture of ciliary localization, trafficking and transduction. Curr Opin Genet Dev 23(4):429–437. doi: 10.1016/j.gde.2013.04.008 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Patel V, Chowdhury R, Igarashi P (2009) Advances in the pathogenesis and treatment of polycystic kidney disease. Curr Opin Nephrol Hypertens 18(2):99–106. doi: 10.1097/MNH.0b013e3283262ab0 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Pazour GJ, Dickert BL, Vucica Y, Seeley ES, Rosenbaum JL, Witman GB, Cole DG (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):709–718CrossRefPubMedPubMedCentralGoogle Scholar
  41. Robert A, Margall-Ducos G, Guidotti JE, Bregerie O, Celati C, Brechot C, Desdouets C (2007) The intraflagellar transport component IFT88/polaris is a centrosomal protein regulating G1-S transition in non-ciliated cells. J Cell Sci 120(Pt 4):628–637. doi: 10.1242/jcs.03366 CrossRefPubMedGoogle Scholar
  42. Satir P, Pedersen LB, Christensen ST (2010) The primary cilium at a glance. J Cell Sci 123(Pt 4):499–503. doi: 10.1242/jcs.050377 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6(1):91–99. doi: 10.1016/j.ccr.2004.06.007 CrossRefPubMedGoogle Scholar
  44. Shibazaki S, Yu Z, Nishio S, Tian X, Thomson RB, Mitobe M, Louvi A, Velazquez H, Ishibe S, Cantley LG, Igarashi P, Somlo S (2008) Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Hum Mol Genet 17(11):1505–1516. doi: 10.1093/hmg/ddn039 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Singla V, Reiter JF (2006) The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science 313(5787):629–633. doi: 10.1126/science.1124534 CrossRefPubMedGoogle Scholar
  46. Smith LA, Bukanov NO, Husson H, Russo RJ, Barry TC, Taylor AL, Beier DR, Ibraghimov-Beskrovnaya O (2006) Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease. J Am Soc Nephrol JASN 17(10):2821–2831. doi: 10.1681/ASN.2006020136 CrossRefPubMedGoogle Scholar
  47. Taschner M, Bhogaraju S, Lorentzen E (2012) Architecture and function of IFT complex proteins in ciliogenesis. Differ Res Biolog Diver 83(2):S12–S22. doi: 10.1016/j.diff.2011.11.001 CrossRefGoogle Scholar
  48. Tran PV, Haycraft CJ, Besschetnova TY, Turbe-Doan A, Stottmann RW, Herron BJ, Chesebro AL, Qiu H, Scherz PJ, Shah JV, Yoder BK, Beier DR (2008) THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet 40(4):403–410. doi: 10.1038/ng.105 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Tsao CC, Gorovsky MA (2008) Tetrahymena IFT122A is not essential for cilia assembly but plays a role in returning IFT proteins from the ciliary tip to the cell body. J Cell Sci 121(Pt 4):428–436. doi: 10.1242/jcs.015826 CrossRefPubMedGoogle Scholar
  50. Waters AM, Beales PL (2011) Ciliopathies: an expanding disease spectrum. Pediatr Nephrol 26(7):1039–1056. doi: 10.1007/s00467-010-1731-7 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Winyard P, Jenkins D (2011) Putative roles of cilia in polycystic kidney disease. Biochim Biophys Acta 1812(10):1256–1262. doi: 10.1016/j.bbadis.2011.04.012 CrossRefPubMedGoogle Scholar
  52. Wrighton KH (2010) Cell signalling: cilia downsize mTORC1. Nat Rev Mol Cell Biol 11(12):820–821. doi: 10.1038/nrm3019 CrossRefPubMedGoogle Scholar
  53. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484. doi: 10.1016/j.cell.2006.01.016 CrossRefPubMedGoogle Scholar
  54. Yamaguchi T, Hempson SJ, Reif GA, Hedge AM, Wallace DP (2006) Calcium restores a normal proliferation phenotype in human polycystic kidney disease epithelial cells. J Am Soc Nephrol JASN 17(1):178–187. doi: 10.1681/ASN.2005060645 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Singapore 2016

Authors and Affiliations

  1. 1.Molecular Medicine Laboratory, Department of Life systemsSookmyung Women’s UniversitySeoulSouth Korea

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