Primary Cilia in Cystic Kidney Disease

  • Prachee Avasthi
  • Robin L. Maser
  • Pamela V. Tran
Part of the Results and Problems in Cell Differentiation book series (RESULTS, volume 60)


Primary cilia are small, antenna-like structures that detect mechanical and chemical cues and transduce extracellular signals. While mammalian primary cilia were first reported in the late 1800s, scientific interest in these sensory organelles has burgeoned since the beginning of the twenty-first century with recognition that primary cilia are essential to human health. Among the most common clinical manifestations of ciliary dysfunction are renal cysts. The molecular mechanisms underlying renal cystogenesis are complex, involving multiple aberrant cellular processes and signaling pathways, while initiating molecular events remain undefined. Autosomal Dominant Polycystic Kidney Disease is the most common renal cystic disease, caused by disruption of polycystin-1 and polycystin-2 transmembrane proteins, which evidence suggests must localize to primary cilia for proper function. To understand how the absence of these proteins in primary cilia may be remediated, we review intracellular trafficking of polycystins to the primary cilium. We also examine the controversial mechanisms by which primary cilia transduce flow-mediated mechanical stress into intracellular calcium. Further, to better understand ciliary function in the kidney, we highlight the LKB1/AMPK, Wnt, and Hedgehog developmental signaling pathways mediated by primary cilia and misregulated in renal cystic disease.


  1. Abdul-Majeed S, Nauli SM (2011) Dopamine receptor type 5 in the primary cilia has dual chemo- and mechano-sensory roles. Hypertension 58:325–331PubMedPubMedCentralCrossRefGoogle Scholar
  2. Abdul-Majeed S, Moloney BC, Nauli SM (2012) Mechanisms regulating cilia growth and cilia function in endothelial cells. Cell Mol Life Sci 69:165–173PubMedCrossRefGoogle Scholar
  3. Afzelius BA (1976) A human syndrome caused by immotile cilia. Science 193:317–319PubMedCrossRefGoogle Scholar
  4. Ait-Lounis A, Baas D, Barras E, Benadiba C, Charollais A, Nlend Nlend R, Liegeois D, Meda P, Durand B, Reith W (2007) Novel function of the ciliogenic transcription factor RFX3 in development of the endocrine pancreas. Diabetes 56:950–959PubMedCrossRefGoogle Scholar
  5. Aldahmesh MA, Li Y, Alhashem A, Anazi S, Alkuraya H, Hashem M, Awaji AA, Sogaty S, Alkharashi A, Alzahrani S et al (2014) IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet–Biedl syndrome. Hum Mol Genet 23:3307–3315PubMedPubMedCentralCrossRefGoogle Scholar
  6. Alten L, Schuster-Gossler K, Beckers A, Groos S, Ulmer B, Hegermann J, Ochs M, Gossler A (2012) Differential regulation of node formation, nodal ciliogenesis and cilia positioning by Noto and Foxj1. Development 139:1276–1284PubMedCrossRefGoogle Scholar
  7. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers ER, Teslovich TM et al (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 425:628–633PubMedCrossRefGoogle Scholar
  8. Attanasio M, Uhlenhaut NH, Sousa VH, O’Toole JF, Otto E, Anlag K, Klugmann C, Treier AC, Helou J, Sayer JA et al (2007) Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nat Genet 39:1018–1024PubMedCrossRefGoogle Scholar
  9. Avasthi P, Marshall WF (2012) Stages of ciliogenesis and regulation of ciliary length. Differ Res Biol Divers 83:S30–S42CrossRefGoogle Scholar
  10. Avasthi P, Marshall W (2013) Ciliary secretion: switching the cellular antenna to ‘transmit’. Curr Biol 23:R471–R473PubMedCrossRefGoogle Scholar
  11. Avasthi P, Marley A, Lin H, Gregori-Puigjane E, Shoichet BK, von Zastrow M, Marshall WF (2012) A chemical screen identifies class a g-protein coupled receptors as regulators of cilia. ACS Chem Biol 7:911–919PubMedPubMedCentralCrossRefGoogle Scholar
  12. Avasthi P, Onishi M, Karpiak J, Yamamoto R, Mackinder L, Jonikas MC, Sale WS, Shoichet B, Pringle JR, Marshall WF (2014) Actin is required for IFT regulation in Chlamydomonas reinhardtii. Curr Biol 24:2025–2032PubMedPubMedCentralCrossRefGoogle Scholar
  13. Barr MM, Sternberg PW (1999) A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature 401:386–389PubMedGoogle Scholar
  14. Beales PL, Bland E, Tobin JL, Bacchelli C, Tuysuz B, Hill J, Rix S, Pearson CG, Kai M, Hartley J et al (2007) IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nat Genet 39:727–729PubMedPubMedCentralCrossRefGoogle Scholar
  15. Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K (2008) Bardet–Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci USA 105:4242–4246PubMedPubMedCentralCrossRefGoogle Scholar
  16. Berman SA, Wilson NF, Haas NA, Lefebvre PA (2003) A novel MAP kinase regulates flagellar length in Chlamydomonas. Curr Biol 13:1145–1149PubMedCrossRefGoogle Scholar
  17. Bershteyn M, Atwood SX, Woo WM, Li M, Oro AE (2010) MIM and cortactin antagonism regulates ciliogenesis and hedgehog signaling. Dev Cell 19:270–283PubMedPubMedCentralCrossRefGoogle Scholar
  18. Besschetnova TY, Kolpakova-Hart E, Guan Y, Zhou J, Olsen BR, Shah JV (2010) Identification of signaling pathways regulating primary cilium length and flow-mediated adaptation. Curr Biol 20:182–187PubMedPubMedCentralCrossRefGoogle Scholar
  19. Blacque OE, Li C, Inglis PN, Esmail MA, Ou G, Mah AK, Baillie DL, Scholey JM, Leroux MR (2006) The WD repeat-containing protein IFTA-1 is required for retrograde intraflagellar transport. Mol Biol Cell 17:5053–5062PubMedPubMedCentralCrossRefGoogle Scholar
  20. Bloodgood RA (2012) The future of ciliary and flagellar membrane research. Mol Biol Cell 23:2407–2411PubMedPubMedCentralCrossRefGoogle Scholar
  21. Boehlke C, Kotsis F, Patel V, Braeg S, Voelker H, Bredt S, Beyer T, Janusch H, Hamann C, Godel M et al (2010) Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat Cell Biol 12:1115–1122PubMedPubMedCentralCrossRefGoogle Scholar
  22. Bonneau D, Raymond F, Kremer C, Klossek JM, Kaplan J, Patte F (1993) Usher syndrome type I associated with bronchiectasis and immotile nasal cilia in two brothers. J Med Genet 30:253–254PubMedPubMedCentralCrossRefGoogle Scholar
  23. Brazelton WJ, Amundsen CD, Silflow CD, Lefebvre PA (2001) The bld1 mutation identifies the Chlamydomonas osm-6 homolog as a gene required for flagellar assembly. Curr Biol 11:1591–1594PubMedCrossRefGoogle Scholar
  24. Broekhuis JR, Leong WY, Jansen G (2013) Regulation of cilium length and intraflagellar transport. Int Rev Cell Mol Biol 303:101–138PubMedCrossRefGoogle Scholar
  25. Bujakowska KM, Zhang Q, Siemiatkowska AM, Liu Q, Place E, Falk MJ, Consugar M, Lancelot ME, Antonio A, Lonjou C et al (2015) Mutations in IFT172 cause isolated retinal degeneration and Bardet–Biedl syndrome. Hum Mol Genet 24:230–242PubMedCrossRefGoogle Scholar
  26. Burghoorn J, Dekkers MP, Rademakers S, de Jong T, Willemsen R, Jansen G (2007) Mutation of the MAP kinase DYF-5 affects docking and undocking of kinesin-2 motors and reduces their speed in the cilia of Caenorhabditis elegans. Proc Natl Acad Sci USA 104:7157–7162PubMedPubMedCentralCrossRefGoogle Scholar
  27. Cai Y, Fedeles SV, Dong K, Anyatonwu G, Onoe T, Mitobe M, Gao JD, Okuhara D, Tian X, Gallagher AR et al (2014) Altered trafficking and stability of polycystins underlie polycystic kidney disease. J Clin Invest 124:5129–5144PubMedPubMedCentralCrossRefGoogle Scholar
  28. Calvet JP (2008) Strategies to inhibit cyst formation in ADPKD. Clin J Am Soc Nephrol CJASN 3:1205–1211PubMedCrossRefGoogle Scholar
  29. Calvet JP, Grantham JJ (2001) The genetics and physiology of polycystic kidney disease. Semin Nephrol 21:107–123PubMedCrossRefGoogle Scholar
  30. Camner P, Mossberg B, Afzelius BA (1975) Evidence of congenitally nonfunctioning cilia in the tracheobronchial tract in two subjects. Am Rev Respir Dis 112:807–809PubMedGoogle Scholar
  31. Cano DA, Murcia NS, Pazour GJ, Hebrok M (2004) Orpk mouse model of polycystic kidney disease reveals essential role of primary cilia in pancreatic tissue organization. Development 131:3457–3467PubMedCrossRefGoogle Scholar
  32. Chan SK, Riley PR, Price KL, McElduff F, Winyard PJ, Welham SJ, Woolf AS, Long DA (2010) Corticosteroid-induced kidney dysmorphogenesis is associated with deregulated expression of known cystogenic molecules, as well as Indian hedgehog. Am J Physiol Renal Physiol 298:F346–F356PubMedCrossRefGoogle Scholar
  33. Chapin HC, Rajendran V, Caplan MJ (2010) Polycystin-1 surface localization is stimulated by polycystin-2 and cleavage at the G protein-coupled receptor proteolytic site. Mol Biol Cell 21:4338–4348PubMedPubMedCentralCrossRefGoogle Scholar
  34. Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hiesberger T, Igarashi P, Bennett AM, Ibraghimov-Beskrovnaya O, Somlo S et al (2004) Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. J Clin Invest 114:1433–1443PubMedPubMedCentralCrossRefGoogle Scholar
  35. Chavez M, Ena S, Van Sande J, de Kerchove d’Exaerde A, Schurmans S, Schiffmann SN (2015) Modulation of ciliary phosphoinositide content regulates trafficking and sonic hedgehog signaling output. Dev Cell 34:338–350PubMedCrossRefGoogle Scholar
  36. Chih B, Liu P, Chinn Y, Chalouni C, Komuves LG, Hass PE, Sandoval W, Peterson AS (2012) A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol 14:61–72CrossRefGoogle Scholar
  37. Choi YH, Suzuki A, Hajarnis S, Ma Z, Chapin HC, Caplan MJ, Pontoglio M, Somlo S, Igarashi P (2011) Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases. Proc Natl Acad Sci USA 108:10679–10684PubMedPubMedCentralCrossRefGoogle Scholar
  38. Christensen ST, Ott CM (2007) Cell signaling. A ciliary signaling switch. Science 317:330–331PubMedCrossRefGoogle Scholar
  39. Coene KL, Mans DA, Boldt K, Gloeckner CJ, van Reeuwijk J, Bolat E, Roosing S, Letteboer SJ, Peters TA, Cremers FP et al (2011) The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase. Hum Mol Genet 20:3592–3605PubMedCrossRefGoogle Scholar
  40. Cogswell C, Price SJ, Hou X, Guay-Woodford LM, Flaherty L, Bryda EC (2003) Positional cloning of jcpk/bpk locus of the mouse. Mamm Genome 14:242–249PubMedCrossRefGoogle Scholar
  41. 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 141:993–1008PubMedPubMedCentralCrossRefGoogle Scholar
  42. Collingridge P, Brownlee C, Wheeler GL (2013) Compartmentalized calcium signaling in cilia regulates intraflagellar transport. Curr Biol 23:2311–2318PubMedCrossRefGoogle Scholar
  43. Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF (2005) Vertebrate Smoothened functions at the primary cilium. Nature 437:1018–1021PubMedCrossRefGoogle Scholar
  44. Corbit KC, Shyer AE, Dowdle WE, Gaulden J, Singla V, Chen MH, Chuang PT, Reiter JF (2008) Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat Cell Biol 10:70–76PubMedCrossRefGoogle Scholar
  45. Craft JM, Harris JA, Hyman S, Kner P, Lechtreck KF (2015) Tubulin transport by IFT is upregulated during ciliary growth by a cilium-autonomous mechanism. J Cell Biol 208:223–237PubMedPubMedCentralCrossRefGoogle Scholar
  46. Davis EE, Zhang Q, Liu Q, Diplas BH, Davey LM, Hartley J, Stoetzel C, Szymanska K, Ramaswami G, Logan CV et al (2011) TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet 43:189–196PubMedPubMedCentralCrossRefGoogle Scholar
  47. Dawe HR, Smith UM, Cullinane AR, Gerrelli D, Cox P, Badano JL, Blair-Reid S, Sriram N, Katsanis N, Attie-Bitach T et al (2007) The Meckel–Gruber syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum Mol Genet 16:173–186PubMedCrossRefGoogle Scholar
  48. 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 11:1586–1590PubMedCrossRefGoogle Scholar
  49. DeCaen PG, Delling M, Vien TN, Clapham DE (2013) Direct recording and molecular identification of the calcium channel of primary cilia. Nature 504:315–318PubMedPubMedCentralCrossRefGoogle Scholar
  50. Delling M, DeCaen PG, Doerner JF, Febvay S, Clapham DE (2013) Primary cilia are specialized calcium signalling organelles. Nature 504:311–314PubMedPubMedCentralCrossRefGoogle Scholar
  51. Delling M, Indzhykulian AA, Liu X, Li Y, Xie T, Corey DP, Clapham DE (2016) Primary cilia are not calcium-responsive mechanosensors. Nature 531:656–660PubMedPubMedCentralCrossRefGoogle Scholar
  52. den Hollander AI, Koenekoop RK, Mohamed MD, Arts HH, Boldt K, Towns KV, Sedmak T, Beer M, Nagel-Wolfrum K, McKibbin M et al (2007) Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis. Nat Genet 39:889–895CrossRefGoogle Scholar
  53. Dentler W (2013) A role for the membrane in regulating Chlamydomonas flagellar length. PLoS One 8:e53366PubMedPubMedCentralCrossRefGoogle Scholar
  54. Eggenschwiler JT, Anderson KV (2007) Cilia and developmental signaling. Annu Rev Cell Dev Biol 23:345–373PubMedPubMedCentralCrossRefGoogle Scholar
  55. Eguether T, San Agustin JT, Keady BT, Jonassen JA, Liang Y, Francis R, Tobita K, Johnson CA, Abdelhamed ZA, Lo CW et al (2014) IFT27 links the BBSome to IFT for maintenance of the ciliary signaling compartment. Dev Cell 31:279–290PubMedPubMedCentralCrossRefGoogle Scholar
  56. Engel BD, Ludington WB, Marshall WF (2009) Intraflagellar transport particle size scales inversely with flagellar length: revisiting the balance-point length control model. J Cell Biol 187:81–89PubMedPubMedCentralCrossRefGoogle Scholar
  57. Esteban MA, Harten SK, Tran MG, Maxwell PH (2006) Formation of primary cilia in the renal epithelium is regulated by the von Hippel–Lindau tumor suppressor protein. J Am Soc Nephrol 17:1801–1806PubMedCrossRefGoogle Scholar
  58. Fogelgren B, Lin SY, Zuo X, Jaffe KM, Park KM, Reichert RJ, Bell PD, Burdine RD, Lipschutz JH (2011) The exocyst protein Sec10 interacts with Polycystin-2 and knockdown causes PKD-phenotypes. PLoS Genet 7:e1001361PubMedPubMedCentralCrossRefGoogle Scholar
  59. 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 17:3781–3792PubMedPubMedCentralCrossRefGoogle Scholar
  60. Franco I, Gulluni F, Campa CC, Costa C, Margaria JP, Ciraolo E, Martini M, Monteyne D, De Luca E, Germena G et al (2014) PI3K class II alpha controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. Dev Cell 28:647–658PubMedPubMedCentralCrossRefGoogle Scholar
  61. Franco I, Margaria JP, De Santis MC, Ranghino A, Monteyne D, Chiaravalli M, Pema M, Campa CC, Ratto E, Gulluni F, Perez-Morga D, Somlo S, Merlo GR, Boletta A, Hirsch E (2016) Phosphoinositide 3-Kinase-C2α regulates polycystin-2 ciliary entry and protects against kidney cyst formation. J Am Soc Nephrol 27(4):1135–1144. doi: 10.1681/ASN.2014100967. Epub 2015 Aug 13CrossRefPubMedPubMedCentralGoogle Scholar
  62. Freedman BS, Lam AQ, Sundsbak JL, Iatrino R, Su X, Koon SJ, Wu M, Daheron L, Harris PC, Zhou J et al (2013) Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1 mutations. J Am Soc Nephrol 24:1571–1586PubMedPubMedCentralCrossRefGoogle Scholar
  63. Fujiwara M, Ishihara T, Katsura I (1999) A novel WD40 protein, CHE-2, acts cell-autonomously in the formation of C. elegans sensory cilia. Development 126:4839–4848PubMedGoogle Scholar
  64. Gainullin VG, Hopp K, Ward CJ, Hommerding CJ, Harris PC (2015) Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner. J Clin Invest 125:607–620PubMedPubMedCentralCrossRefGoogle Scholar
  65. Gallagher AR, Esquivel EL, Briere TS, Tian X, Mitobe M, Menezes LF, Markowitz GS, Jain D, Onuchic LF, Somlo S (2008) Biliary and pancreatic dysgenesis in mice harboring a mutation in Pkhd1. Am J Pathol 172:417–429PubMedPubMedCentralCrossRefGoogle Scholar
  66. Garcia-Gonzalez MA, Menezes LF, Piontek KB, Kaimori J, Huso DL, Watnick T, Onuchic LF, Guay-Woodford LM, Germino GG (2007) Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway. Hum Mol Genet 16:1940–1950PubMedPubMedCentralCrossRefGoogle Scholar
  67. Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G, Otto EA, Noriega TR, Seol AD, Robinson JF, Bennett CL, Josifova DJ et al (2011) A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet 43:776–784PubMedPubMedCentralCrossRefGoogle Scholar
  68. Garcia-Gonzalo FR, Phua SC, Roberson EC, Garcia G 3rd, Abedin M, Schurmans S, Inoue T, Reiter JF (2015) Phosphoinositides Regulate ciliary protein trafficking to modulate hedgehog signaling. Dev Cell 34:400–409PubMedPubMedCentralCrossRefGoogle Scholar
  69. Gattone VH 2nd, Wang X, Harris PC, Torres VE (2003) Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 9:1323–1326PubMedCrossRefGoogle Scholar
  70. Geng L, Okuhara D, Yu Z, Tian X, Cai Y, Shibazaki S, Somlo S (2006) Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif. J Cell Sci 119:1383–1395PubMedCrossRefGoogle Scholar
  71. Guo DF, Rahmouni K (2011) Molecular basis of the obesity associated with Bardet–Biedl syndrome. Trends Endocrinol Metab TEM 22:286–293PubMedGoogle Scholar
  72. Guo DF, Cui H, Zhang Q, Morgan DA, Thedens DR, Nishimura D, Grobe JL, Sheffield VC, Rahmouni K (2016) The BBSome controls energy homeostasis by mediating the transport of the leptin receptor to the plasma membrane. PLoS Genet 12:e1005890PubMedPubMedCentralCrossRefGoogle Scholar
  73. Han SJ, Jang HS, Kim JI, Lipschutz JH, Park KM (2016) Unilateral nephrectomy elongates primary cilia in the remaining kidney via reactive oxygen species. Sci Rep 6:22281PubMedPubMedCentralCrossRefGoogle Scholar
  74. Han YM, Kang GM, Byun K, Ko HW, Kim J, Shin MS, Kim HK, Gil SY, Yu JH, Lee B et al (2014) Leptin-promoted cilia assembly is critical for normal energy balance. J Clin Investig 124:2193–2197PubMedPubMedCentralCrossRefGoogle Scholar
  75. Hartman TR, Liu D, Zilfou JT, Robb V, Morrison T, Watnick T, Henske EP (2009) The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway. Hum Mol Genet 18:151–163PubMedCrossRefGoogle Scholar
  76. Hatayama M, Mikoshiba K, Aruga J (2011) IP3 signaling is required for cilia formation and left–right body axis determination in Xenopus embryos. Biochem Biophys Res Commun 410:520–524PubMedCrossRefGoogle Scholar
  77. Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1:e53PubMedPubMedCentralCrossRefGoogle Scholar
  78. Haycraft CJ, Schafer JC, Zhang Q, Taulman PD, Yoder BK (2003) Identification of CHE-13, a novel intraflagellar transport protein required for cilia formation. Exp Cell Res 284:251–263PubMedCrossRefGoogle Scholar
  79. He M, Subramanian R, Bangs F, Omelchenko T, Liem KF Jr, Kapoor TM, Anderson KV (2014) The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment. Nat Cell Biol 16:663–672PubMedPubMedCentralCrossRefGoogle Scholar
  80. Hearn T, Spalluto C, Phillips VJ, Renforth GL, Copin N, Hanley NA, Wilson DI (2005) Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Diabetes 54:1581–1587PubMedCrossRefGoogle Scholar
  81. Heon E, Kim G, Qin S, Garrison JE, Tavares E, Vincent A, Nuangchamnong N, Scott CA, Slusarski DC, Sheffield VC (2016) Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21). Hum Mol Genet 25(11):2283–2294. Epub 2016 Mar 22PubMedPubMedCentralCrossRefGoogle Scholar
  82. Hilton LK, Gunawardane K, Kim JW, Schwarz MC, Quarmby LM (2013) The kinases LF4 and CNK2 control ciliary length by feedback regulation of assembly and disassembly rates. Curr Biol 23:2208–2214PubMedCrossRefGoogle Scholar
  83. Hoffmeister H, Babinger K, Gurster S, Cedzich A, Meese C, Schadendorf K, Osten L, de Vries U, Rascle A, Witzgall R (2011) Polycystin-2 takes different routes to the somatic and ciliary plasma membrane. J Cell Biol 192:631–645PubMedPubMedCentralCrossRefGoogle Scholar
  84. Hogan MC, Manganelli L, Woollard JR, Masyuk AI, Masyuk TV, Tammachote R, Huang BQ, Leontovich AA, Beito TG, Madden BJ et al (2009) Characterization of PKD protein-positive exosome-like vesicles. J Am Soc Nephrol 20:278–288PubMedPubMedCentralCrossRefGoogle Scholar
  85. Hong DH, Yue G, Adamian M, Li T (2001) Retinitis pigmentosa GTPase regulator (RPGRr)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting cilium. J Biol Chem 276:12091–12099PubMedCrossRefGoogle Scholar
  86. Hopp K, Hommerding CJ, Wang X, Ye H, Harris PC, Torres VE (2015) Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J Am Soc Nephrol 26:39–47PubMedCrossRefGoogle Scholar
  87. Hopp K, Ward CJ, Hommerding CJ, Nasr SH, Tuan HF, Gainullin VG, Rossetti S, Torres VE, Harris PC (2012) Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J Clin Invest 122:4257–4273PubMedPubMedCentralCrossRefGoogle Scholar
  88. Hsiao YC, Tuz K, Ferland RJ (2012) Trafficking in and to the primary cilium. Cilia 1:4PubMedPubMedCentralCrossRefGoogle Scholar
  89. Hu J, Wittekind SG, Barr MM (2007) STAM and Hrs down-regulate ciliary TRP receptors. Mol Biol Cell 18:3277–3289PubMedPubMedCentralCrossRefGoogle Scholar
  90. Huangfu D, Anderson KV (2005) Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA 102:11325–11330PubMedPubMedCentralCrossRefGoogle Scholar
  91. Huangfu D, Liu A, Rakeman AS, Murcia NS, Niswander L, Anderson KV (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426:83–87PubMedCrossRefGoogle Scholar
  92. Husson H, Moreno S, Smith LA, Smith MM, Russo RJ, Pitstick R, Sergeev M, Ledbetter SR, Bukanov NO, Lane M et al (2016) Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis. Hum Mol Genet 25(11):2245–2255. Epub 2016 Apr 5PubMedPubMedCentralCrossRefGoogle Scholar
  93. Ibraghimov-Beskrovnaya O, Natoli TA (2011) mTOR signaling in polycystic kidney disease. Trends Mol Med 17:625–633PubMedCrossRefGoogle Scholar
  94. Ingham PW, Nakano Y, Seger C (2011) Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet 12:393–406PubMedCrossRefGoogle Scholar
  95. Iomini C, Babaev-Khaimov V, Sassaroli M, Piperno G (2001) Protein particles in Chlamydomonas flagella undergo a transport cycle consisting of four phases. J Cell Biol 153:13–24PubMedPubMedCentralCrossRefGoogle Scholar
  96. Iomini C, Li L, Esparza JM, Dutcher SK (2009) Retrograde intraflagellar transport mutants identify complex A proteins with multiple genetic interactions in Chlamydomonas reinhardtii. Genetics 183:885–896PubMedPubMedCentralCrossRefGoogle Scholar
  97. Ishikawa H, Ide T, Yagi T, Jiang X, Hirono M, Sasaki H, Yanagisawa H, Wemmer KA, Stainier DY, Qin H et al (2014) TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella. Elife 3:e01566PubMedPubMedCentralGoogle Scholar
  98. Jacoby M, Cox JJ, Gayral S, Hampshire DJ, Ayub M, Blockmans M, Pernot E, Kisseleva MV, Compere P, Schiffmann SN et al (2009) INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet 41:1027–1031PubMedCrossRefGoogle Scholar
  99. Jin X, Mohieldin AM, Muntean BS, Green JA, Shah JV, Mykytyn K, Nauli SM (2014a) Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli. Cell Mol Life Sci 71:2165–2178PubMedCrossRefGoogle Scholar
  100. Jin X, Muntean BS, Aal-Aaboda MS, Duan Q, Zhou J, Nauli SM (2014b) L-type calcium channel modulates cystic kidney phenotype. Biochim Biophys Acta 1842(9):1518–1526. doi: 10.1016/j.bbadis.2014.06.001. Epub 2014 Jun 9CrossRefGoogle Scholar
  101. 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 183:377–384PubMedPubMedCentralCrossRefGoogle Scholar
  102. 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 23:641–651PubMedPubMedCentralCrossRefGoogle Scholar
  103. 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 22:940–951PubMedPubMedCentralCrossRefGoogle Scholar
  104. Keeling J, Tsiokas L, Maskey D (2016) Cellular mechanisms of ciliary length control. Cells 5Google Scholar
  105. Khan SA, Muhammad N, Khan MA, Kamal A, Rehman ZU, Khan S (2016) Genetics of human Bardet–Biedl syndrome, an updates. Clin Genet 90(1):3–15. doi: 10.1111/cge.12737. Epub 2016 Feb 9CrossRefPubMedGoogle Scholar
  106. Khayyeri H, Barreto S, Lacroix D (2015) Primary cilia mechanics affects cell mechanosensation: a computational study. J Theor Biol 379:38–46PubMedCrossRefGoogle Scholar
  107. Kim JH, Ki SM, Joung JG, Scott E, Heynen-Genel S, Aza-Blanc P, Kwon CH, Kim J, Gleeson JG, Lee JE (2016a) Genome-wide screen identifies novel machineries required for both ciliogenesis and cell cycle arrest upon serum starvation. Biochim Biophys Acta 1863:1307–1318PubMedPubMedCentralCrossRefGoogle Scholar
  108. Kim S, Lee K, Choi JH, Ringstad N, Dynlacht BD (2015) Nek2 activation of Kif24 ensures cilium disassembly during the cell cycle. Nat Commun 6:8087PubMedPubMedCentralCrossRefGoogle Scholar
  109. Kim J, Lee JE, Heynen-Genel S, Suyama E, Ono K, Lee K, Ideker T, Aza-Blanc P, Gleeson JG (2010) Functional genomic screen for modulators of ciliogenesis and cilium length. Nature 464:1048–1051PubMedPubMedCentralCrossRefGoogle Scholar
  110. Kim S, Nie H, Nesin V, Tran U, Outeda P, Bai CX, Keeling J, Maskey D, Watnick T, Wessely O et al (2016b) The polycystin complex mediates Wnt/Ca signalling. Nat Cell Biol 18(7):752–764. doi: 10.1038/ncb3363. Epub 2016 May 23CrossRefPubMedPubMedCentralGoogle Scholar
  111. Kim H, Xu H, Yao Q, Li W, Huang Q, Outeda P, Cebotaru V, Chiaravalli M, Boletta A, Piontek K et al (2014) Ciliary membrane proteins traffic through the Golgi via a Rabep1/GGA1/Arl3-dependent mechanism. Nat Commun 5:5482PubMedPubMedCentralCrossRefGoogle Scholar
  112. Knodler A, Feng S, Zhang J, Zhang X, Das A, Peranen J, Guo W (2010) Coordination of Rab8 and Rab11 in primary ciliogenesis. Proc Natl Acad Sci USA 107:6346–6351PubMedPubMedCentralCrossRefGoogle Scholar
  113. Kottgen M, Buchholz B, Garcia-Gonzalez MA, Kotsis F, Fu X, Doerken M, Boehlke C, Steffl D, Tauber R, Wegierski T et al (2008) TRPP2 and TRPV4 form a polymodal sensory channel complex. J Cell Biol 182:437–447PubMedPubMedCentralCrossRefGoogle Scholar
  114. Kozminski KG, Beech PL, Rosenbaum JL (1995) The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane. J Cell Biol 131:1517–1527PubMedCrossRefGoogle Scholar
  115. Kozminski KG, Johnson KA, Forscher P, Rosenbaum JL (1993) A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc Natl Acad Sci USA 90:5519–5523PubMedPubMedCentralCrossRefGoogle Scholar
  116. Kurbegovic A, Kim H, Xu H, Yu S, Cruanes J, Maser RL, Boletta A, Trudel M, Qian F (2014) Novel functional complexity of polycystin-1 by GPS cleavage in vivo: role in polycystic kidney disease. Mol Cell Biol 34:3341–3353PubMedPubMedCentralCrossRefGoogle Scholar
  117. Lal M, Song X, Pluznick JL, Di Giovanni V, Merrick DM, Rosenblum ND, Chauvet V, Gottardi CJ, Pei Y, Caplan MJ (2008) Polycystin-1 C-terminal tail associates with beta-catenin and inhibits canonical Wnt signaling. Hum Mol Genet 17:3105–3117PubMedPubMedCentralCrossRefGoogle Scholar
  118. Lancaster MA, Louie CM, Silhavy JL, Sintasath L, Decambre M, Nigam SK, Willert K, Gleeson JG (2009) Impaired Wnt-beta-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy. Nat Med 15:1046–1054PubMedPubMedCentralCrossRefGoogle Scholar
  119. Lancaster MA, Schroth J, Gleeson JG (2011) Subcellular spatial regulation of canonical Wnt signalling at the primary cilium. Nat Cell Biol 13:700–707PubMedPubMedCentralCrossRefGoogle Scholar
  120. Lavagnino M, Gardner K, Sedlak AM, Arnoczky SP (2013) Tendon cell ciliary length as a biomarker of in situ cytoskeletal tensional homeostasis. Muscles Ligaments Tendons J 3:118–121PubMedPubMedCentralGoogle Scholar
  121. Lechtreck KF, Johnson EC, Sakai T, Cochran D, Ballif BA, Rush J, Pazour GJ, Ikebe M, Witman GB (2009) The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J Cell Biol 187:1117–1132PubMedPubMedCentralCrossRefGoogle Scholar
  122. Leightner AC, Hommerding CJ, Peng Y, Salisbury JL, Gainullin VG, Czarnecki PG, Sussman CR, Harris PC (2013) The Meckel syndrome protein meckelin (TMEM67) is a key regulator of cilia function but is not required for tissue planar polarity. Hum Mol Genet 22:2024–2040PubMedPubMedCentralCrossRefGoogle Scholar
  123. Li B, Rauhauser AA, Dai J, Sakthivel R, Igarashi P, Jetten AM, Attanasio M (2011) Increased hedgehog signaling in postnatal kidney results in aberrant activation of nephron developmental programs. Hum Mol Genet 20(21):4155–4166. doi: 10.1093/hmg/ddr339 CrossRefPubMedPubMedCentralGoogle Scholar
  124. Liew GM, Ye F, Nager AR, Murphy JP, Lee JS, Aguiar M, Breslow DK, Gygi SP, Nachury MV (2014) The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Dev Cell 31:265–278PubMedPubMedCentralCrossRefGoogle Scholar
  125. 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 USA 100:5286–5291PubMedPubMedCentralCrossRefGoogle Scholar
  126. Lindstrand A, Davis EE, Carvalho CM, Pehlivan D, Willer JR, Tsai IC, Ramanathan S, Zuppan C, Sabo A, Muzny D et al (2014) Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet–Biedl syndrome. Am J Hum Genet 94:745–754PubMedPubMedCentralCrossRefGoogle Scholar
  127. Liu W, Murcia NS, Duan Y, Weinbaum S, Yoder BK, Schwiebert E, Satlin LM (2005b) Mechanoregulation of intracellular Ca2+ concentration is attenuated in collecting duct of monocilium-impaired orpk mice. Am J Physiol Renal Physiol 289:F978–F988PubMedCrossRefGoogle Scholar
  128. Liu A, Wang B, Niswander LA (2005a) Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 132:3103–3111PubMedCrossRefGoogle Scholar
  129. Liu W, Xu S, Woda C, Kim P, Weinbaum S, Satlin LM (2003) Effect of flow and stretch on the [Ca2+]i response of principal and intercalated cells in cortical collecting duct. Am J Physiol Renal Physiol 285:F998–F1012PubMedCrossRefGoogle Scholar
  130. Louie CM, Gleeson JG (2005) Genetic basis of Joubert syndrome and related disorders of cerebellar development. Hum Mol Genet 14 Spec No. 2:R235–R242PubMedCrossRefGoogle Scholar
  131. Low SH, Vasanth S, Larson CH, Mukherjee S, Sharma N, Kinter MT, Kane ME, Obara T, Weimbs T (2006) Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Dev Cell 10:57–69PubMedCrossRefGoogle Scholar
  132. Lu Q, Insinna C, Ott C, Stauffer J, Pintado PA, Rahajeng J, Baxa U, Walia V, Cuenca A, Hwang YS et al (2015) Early steps in primary cilium assembly require EHD1/EHD3-dependent ciliary vesicle formation. Nat Cell Biol 17:531PubMedCrossRefGoogle Scholar
  133. Ludington WB, Wemmer KA, Lechtreck KF, Witman GB, Marshall WF (2013) Avalanche-like behavior in ciliary import. Proc Natl Acad Sci USA 110:3925–3930PubMedPubMedCentralCrossRefGoogle Scholar
  134. Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL et al (2013) Birt–Hogg–Dube syndrome is a novel ciliopathy. Hum Mol Genet 22:4383–4397PubMedPubMedCentralCrossRefGoogle Scholar
  135. Luo N, Lu J, Sun Y (2012) Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish. Vis Res 75:98–107PubMedPubMedCentralCrossRefGoogle Scholar
  136. 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 45:1004–1012PubMedPubMedCentralCrossRefGoogle Scholar
  137. Manning DK, Sergeev M, van Heesbeen RG, Wong MD, Oh JH, Liu Y, Henkelman RM, Drummond I, Shah JV, Beier DR (2013) Loss of the ciliary kinase Nek8 causes left–right asymmetry defects. J Am Soc Nephrol 24:100–112PubMedCrossRefGoogle Scholar
  138. Marion V, Stoetzel C, Schlicht D, Messaddeq N, Koch M, Flori E, Danse JM, Mandel JL, Dollfus H (2009) Transient ciliogenesis involving Bardet–Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation. Proc Natl Acad Sci USA 106:1820–1825PubMedPubMedCentralCrossRefGoogle Scholar
  139. Marion V, Stutzmann F, Gerard M, De Melo C, Schaefer E, Claussmann A, Helle S, Delague V, Souied E, Barrey C et al (2012) Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet–Biedl syndrome with situs inversus and insertional polydactyly. J Med Genet 49:317–321PubMedCrossRefGoogle Scholar
  140. Marshall WF, Rosenbaum JL (2001) Intraflagellar transport balances continuous turnover of outer doublet microtubules: implications for flagellar length control. J Cell Biol 155:405–414PubMedPubMedCentralCrossRefGoogle Scholar
  141. Marshall WF, Qin H, Rodrigo Brenni M, Rosenbaum JL (2005) Flagellar length control system: testing a simple model based on intraflagellar transport and turnover. Mol Biol Cell 16:270–278PubMedPubMedCentralCrossRefGoogle Scholar
  142. Masyuk AI, Masyuk TV, LaRusso NF (2008) Cholangiocyte primary cilia in liver health and disease. Dev Dyn 237:2007–2012PubMedPubMedCentralCrossRefGoogle Scholar
  143. Mattera R, Arighi CN, Lodge R, Zerial M, Bonifacino JS (2003) Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5 complex. EMBO J 22:78–88PubMedPubMedCentralCrossRefGoogle Scholar
  144. Mazelova J, Astuto-Gribble L, Inoue H, Tam BM, Schonteich E, Prekeris R, Moritz OL, Randazzo PA, Deretic D (2009) Ciliary targeting motif VxPx directs assembly of a trafficking module through Arf4. EMBO J 28:183–192PubMedPubMedCentralCrossRefGoogle Scholar
  145. Merrick D, Chapin H, Baggs JE, Yu Z, Somlo S, Sun Z, Hogenesch JB, Caplan MJ (2012) The gamma-secretase cleavage product of polycystin-1 regulates TCF and CHOP-mediated transcriptional activation through a p300-dependent mechanism. Dev Cell 22:197–210PubMedCrossRefGoogle Scholar
  146. Mick DU, Rodrigues RB, Leib RD, Adams CM, Chien AS, Gygi SP, Nachury MV (2015) Proteomics of primary cilia by proximity labeling. Dev Cell 35:497–512PubMedPubMedCentralCrossRefGoogle Scholar
  147. Miller MM, Iglesias DM, Zhang Z, Corsini R, Chu L, Murawski I, Gupta I, Somlo S, Germino GG, Goodyer PR (2011) T-cell factor/beta-catenin activity is suppressed in two different models of autosomal dominant polycystic kidney disease. Kidney Int 80:146–153PubMedCrossRefGoogle Scholar
  148. Mitchell DR (2007) The evolution of eukaryotic cilia and flagella as motile and sensory organelles. Adv Exp Med Biol 607:130–140PubMedPubMedCentralCrossRefGoogle Scholar
  149. Moser M, Matthiesen S, Kirfel J, Schorle H, Bergmann C, Senderek J, Rudnik-Schoneborn S, Zerres K, Buettner R (2005) A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD). Hepatology 41:1113–1121PubMedCrossRefGoogle Scholar
  150. Mukhopadhyay S, Wen X, Chih B, Nelson CD, Lane WS, Scales SJ, Jackson PK (2010) TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia. Genes Dev 24:2180–2193PubMedPubMedCentralCrossRefGoogle Scholar
  151. Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peranen J, Merdes A, Slusarski DC, Scheller RH, Bazan JF, Sheffield VC et al (2007) A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129:1201–1213PubMedCrossRefGoogle Scholar
  152. Nakamura T, Saito D, Kawasumi A, Shinohara K, Asai Y, Takaoka K, Dong F, Takamatsu A, Belo JA, Mochizuki A et al (2012) Fluid flow and interlinked feedback loops establish left–right asymmetric decay of Cerl2 mRNA. Nat Commun 3:1322PubMedCrossRefGoogle Scholar
  153. Natoli TA, Gareski TC, Dackowski WR, Smith L, Bukanov NO, Russo RJ, Husson H, Matthews D, Piepenhagen P, Ibraghimov-Beskrovnaya O (2008) Pkd1 and Nek8 mutations affect cell-cell adhesion and cilia in cysts formed in kidney organ cultures. Am J Physiol Renal Physiol 294:F73–F83PubMedCrossRefGoogle Scholar
  154. Natoli TA, Smith LA, Rogers KA, Wang B, Komarnitsky S, Budman Y, Belenky A, Bukanov NO, Dackowski WR, Husson H et al (2010) Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat Med 16:788–792PubMedPubMedCentralCrossRefGoogle Scholar
  155. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ et al (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137PubMedCrossRefGoogle Scholar
  156. Niewiadomski P, Kong JH, Ahrends R, Ma Y, Humke EW, Khan S, Teruel MN, Novitch BG, Rohatgi R (2014) Gli protein activity is controlled by multisite phosphorylation in vertebrate hedgehog signaling. Cell Rep 6:168–181PubMedCrossRefGoogle Scholar
  157. 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 23:429–437PubMedPubMedCentralCrossRefGoogle Scholar
  158. O’Connor AK, Malarkey EB, Berbari NF, Croyle MJ, Haycraft CJ, Bell PD, Hohenstein P, Kesterson RA, Yoder BK (2013) An inducible CiliaGFP mouse model for in vivo visualization and analysis of cilia in live tissue. Cilia 2:8PubMedPubMedCentralCrossRefGoogle Scholar
  159. Oh EC, Katsanis N (2013) Context-dependent regulation of Wnt signaling through the primary cilium. J Am Soc Nephrol 24:10–18PubMedCrossRefGoogle Scholar
  160. Oishi I, Kawakami Y, Raya A, Callol-Massot C, Izpisua Belmonte JC (2006) Regulation of primary cilia formation and left–right patterning in zebrafish by a noncanonical Wnt signaling mediator, duboraya. Nat Genet 38:1316–1322PubMedCrossRefGoogle Scholar
  161. Olsan EE, Mukherjee S, Wulkersdorfer B, Shillingford JM, Giovannone AJ, Todorov G, Song X, Pei Y, Weimbs T (2011) Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease. Proc Natl Acad Sci USA 108:18067–18072PubMedPubMedCentralCrossRefGoogle Scholar
  162. Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, Muerb U, O’Toole JF, Helou J, Attanasio M et al (2005) Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior–Loken syndrome and interacts with RPGR and calmodulin. Nat Genet 37:282–288PubMedCrossRefGoogle Scholar
  163. Otto EA, Schermer B, Obara T, O’Toole JF, Hiller KS, Mueller AM, Ruf RG, Hoefele J, Beekmann F, Landau D et al (2003) Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left–right axis determination. Nat Genet 34:413–420PubMedPubMedCentralCrossRefGoogle Scholar
  164. Ou Y, Ruan Y, Cheng M, Moser JJ, Rattner JB, van der Hoorn FA (2009) Adenylate cyclase regulates elongation of mammalian primary cilia. Exp Cell Res 315:2802–2817PubMedPubMedCentralCrossRefGoogle Scholar
  165. Pandit MM, Gao Y, van Hoek A, Kohan DE (2015) Osmolar regulation of endothelin-1 production by the inner medullary collecting duct. Life Sci 159:135–139. doi: 10.1016/j.lfs.2015.10.037. Epub 2015 Nov 10CrossRefPubMedGoogle Scholar
  166. Parker JD, Quarmby LM (2003) Chlamydomonas fla mutants reveal a link between deflagellation and intraflagellar transport. BMC Cell Biol 4:11PubMedPubMedCentralCrossRefGoogle Scholar
  167. 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 151:709–718PubMedPubMedCentralCrossRefGoogle Scholar
  168. Pazour GJ, Dickert BL, Witman GB (1999) The DHC1b (DHC2) isoform of cytoplasmic dynein is required for flagellar assembly. J Cell Biol 144:473–481PubMedPubMedCentralCrossRefGoogle Scholar
  169. Pazour GJ, Wilkerson CG, Witman GB (1998) A dynein light chain is essential for the retrograde particle movement of intraflagellar transport (IFT). J Cell Biol 141:979–992PubMedPubMedCentralCrossRefGoogle Scholar
  170. Pedersen LB, Miller MS, Geimer S, Leitch JM, Rosenbaum JL, Cole DG (2005) Chlamydomonas IFT172 is encoded by FLA11, interacts with CrEB1, and regulates IFT at the flagellar tip. Curr Biol 15:262–266PubMedCrossRefGoogle Scholar
  171. Perkins LA, Hedgecock EM, Thomson JN, Culotti JG (1986) Mutant sensory cilia in the nematode Caenorhabditis elegans. Dev Biol 117:456–487PubMedCrossRefGoogle Scholar
  172. Pescio LG, Favale NO, Marquez MG, Sterin-Speziale NB (2012) Glycosphingolipid synthesis is essential for MDCK cell differentiation. Biochim Biophys Acta 1821:884–894PubMedCrossRefGoogle Scholar
  173. Piao T, Luo M, Wang L, Guo Y, Li D, Li P, Snell WJ, Pan J (2009) A microtubule depolymerizing kinesin functions during both flagellar disassembly and flagellar assembly in Chlamydomonas. Proc Natl Acad Sci USA 106:4713–4718PubMedPubMedCentralCrossRefGoogle Scholar
  174. Piontek K, Menezes LF, Garcia-Gonzalez MA, Huso DL, Germino GG (2007) A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med 13:1490–1495PubMedPubMedCentralCrossRefGoogle Scholar
  175. Poole CA, Flint MH, Beaumont BW (1985) Analysis of the morphology and function of primary cilia in connective tissues: a cellular cybernetic probe? Cell Motil 5:175–193PubMedCrossRefGoogle Scholar
  176. Porath B, Gainullin VG, Cornec-Le Gall E, Dillinger EK, Heyer CM, Hopp K, Edwards ME, Madsen CD, Mauritz SR, Banks CJ et al (2016) Mutations in GANAB, encoding the glucosidase IIalpha subunit, cause autosomal-dominant polycystic kidney and liver disease. Am J Hum Genet 98:1193–1207PubMedPubMedCentralCrossRefGoogle Scholar
  177. Porter ME, Bower R, Knott JA, Byrd P, Dentler W (1999) Cytoplasmic dynein heavy chain 1b is required for flagellar assembly in Chlamydomonas. Mol Biol Cell 10:693–712PubMedPubMedCentralCrossRefGoogle Scholar
  178. Praetorius HA, Spring KR (2001) Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol 184:71–79PubMedCrossRefGoogle Scholar
  179. Praetorius HA, Spring KR (2003) Removal of the MDCK cell primary cilium abolishes flow sensing. J Membr Biol 191:69–76PubMedCrossRefGoogle Scholar
  180. Pugacheva EN, Jablonski SA, Hartman TR, Henske EP, Golemis EA (2007) HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129:1351–1363PubMedPubMedCentralCrossRefGoogle Scholar
  181. Qian CN, Knol J, Igarashi P, Lin F, Zylstra U, Teh BT, Williams BO (2005) Cystic renal neoplasia following conditional inactivation of apc in mouse renal tubular epithelium. J Biol Chem 280:3938–3945PubMedCrossRefGoogle Scholar
  182. Qin J, Lin Y, Norman RX, Ko HW, Eggenschwiler JT (2011) Intraflagellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components. Proc Natl Acad Sci USA 108:1456–1461PubMedPubMedCentralCrossRefGoogle Scholar
  183. Qin S, Taglienti M, Cai L, Zhou J, Kreidberg JA (2012) c-Met and NF-kappaB-dependent overexpression of Wnt7a and -7b and Pax2 promotes cystogenesis in polycystic kidney disease. J Am Soc Nephrol 23:1309–1318PubMedPubMedCentralCrossRefGoogle Scholar
  184. Qin S, Taglienti M, Nauli SM, Contrino L, Takakura A, Zhou J, Kreidberg JA (2010) Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease. J Clin Invest 120:3617–3628PubMedPubMedCentralCrossRefGoogle Scholar
  185. Qin H, Wang Z, Diener D, Rosenbaum J (2007) Intraflagellar transport protein 27 is a small G protein involved in cell-cycle control. Curr Biol 17:193–202PubMedPubMedCentralCrossRefGoogle Scholar
  186. Quinlan RJ, Tobin JL, Beales PL (2008) Modeling ciliopathies: primary cilia in development and disease. Curr Top Dev Biol 84:249–310PubMedCrossRefGoogle Scholar
  187. Ravichandran K, Zafar I, Ozkok A, Edelstein CL (2015) An mTOR kinase inhibitor slows disease progression in a rat model of polycystic kidney disease. Nephrol Dial Transplant 30:45–53PubMedCrossRefGoogle Scholar
  188. Rohatgi R, Milenkovic L, Scott MP (2007) Patched1 regulates hedgehog signaling at the primary cilium. Science 317:372–376PubMedCrossRefGoogle Scholar
  189. Romio L, Fry AM, Winyard PJ, Malcolm S, Woolf AS, Feather SA (2004) OFD1 is a centrosomal/basal body protein expressed during mesenchymal-epithelial transition in human nephrogenesis. J Am Soc Nephrol 15:2556–2568PubMedCrossRefGoogle Scholar
  190. Rosenbaum JL, Child FM (1967) Flagellar regeneration in protozoan flagellates. J Cell Biol 34:345–364PubMedPubMedCentralCrossRefGoogle Scholar
  191. Rosenbaum JL, Witman GB (2002) Intraflagellar transport. Nat Rev Mol Cell Biol 3:813–825PubMedCrossRefGoogle Scholar
  192. Ruggenenti P, Gentile G, Perico N, Perna A, Barcella L, Trillini M, Cortinovis M, Ferrer Siles CP, Reyes Loaeza JA, Aparicio MC et al (2016) Effect of sirolimus on disease progression in patients with autosomal dominant polycystic kidney disease and CKD stages 3b-4. Clin J Am Soc Nephrol 11(5):785–794. doi: 10.2215/CJN.09900915. Epub 2016 Feb 22CrossRefPubMedPubMedCentralGoogle Scholar
  193. Ruiz-Perez VL, Goodship JA (2009) Ellis-van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to hedgehog ligands. Am J Med Genet C Semin Med Genet 151C:341–351PubMedCrossRefGoogle Scholar
  194. Rydholm S, Zwartz G, Kowalewski JM, Kamali-Zare P, Frisk T, Brismar H (2010) Mechanical properties of primary cilia regulate the response to fluid flow. Am J Physiol Renal Physiol 298:F1096–F1102PubMedCrossRefGoogle Scholar
  195. Saadi-Kheddouci S, Berrebi D, Romagnolo B, Cluzeaud F, Peuchmaur M, Kahn A, Vandewalle A, Perret C (2001) Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 20:5972–5981PubMedCrossRefGoogle Scholar
  196. Sanchez de Diego A, Alonso Guerrero A, Martinez AC, van Wely KH (2014) Dido3-dependent HDAC6 targeting controls cilium size. Nat Commun 5:3500PubMedGoogle Scholar
  197. Saraga-Babic M, Vukojevic K, Bocina I, Drnasin K, Saraga M (2012) Ciliogenesis in normal human kidney development and post-natal life. Pediatr Nephrol 27:55–63PubMedCrossRefGoogle Scholar
  198. Schaefer E, Stoetzel C, Scheidecker S, Geoffroy V, Prasad MK, Redin C, Missotte I, Lacombe D, Mandel JL, MullerJ et al (2016) Identification of a novel mutation confirms the implication of IFT172 (BBS20) in Bardet–Biedl syndrome. J Hum Genet 61(5):447–450. doi: 10.1038/jhg.2015.162. Epub 2016 Jan 14CrossRefPubMedGoogle Scholar
  199. Scheidecker S, Etard C, Pierce NW, Geoffroy V, Schaefer E, Muller J, Chennen K, Flori E, Pelletier V, Poch O et al (2014) Exome sequencing of Bardet–Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18). J Med Genet 51:132–136PubMedCrossRefGoogle Scholar
  200. Schwarz N, Hardcastle AJ, Cheetham ME (2012) Arl3 and RP2 mediated assembly and traffic of membrane associated cilia proteins. Vis Res 75:2–4PubMedCrossRefGoogle Scholar
  201. Seo S, Baye LM, Schulz NP, Beck JS, Zhang Q, Slusarski DC, Sheffield VC (2010) BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc Natl Acad Sci USA 107:1488–1493PubMedPubMedCentralCrossRefGoogle Scholar
  202. Seo S, Zhang Q, Bugge K, Breslow DK, Searby CC, Nachury MV, Sheffield VC (2011) A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened. PLoS Genet 7:e1002358PubMedPubMedCentralCrossRefGoogle Scholar
  203. Serra AL, Poster D, Kistler AD, Krauer F, Raina S, Young J, Rentsch KM, Spanaus KS, Senn O, Kristanto P et al (2010) Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med 363:820–829PubMedCrossRefGoogle Scholar
  204. Shao YY, Wang L, Welter JF, Ballock RT (2012) Primary cilia modulate Ihh signal transduction in response to hydrostatic loading of growth plate chondrocytes. Bone 50:79–84PubMedCrossRefGoogle Scholar
  205. Sharma N, Kosan ZA, Stallworth JE, Berbari NF, Yoder BK (2011) Soluble levels of cytosolic tubulin regulate ciliary length control. Mol Biol Cell 22:806–816PubMedPubMedCentralCrossRefGoogle Scholar
  206. Shillingford JM, Leamon CP, Vlahov IR, Weimbs T (2012) Folate-conjugated rapamycin slows progression of polycystic kidney disease. J Am Soc Nephrol 23:1674–1681PubMedPubMedCentralCrossRefGoogle Scholar
  207. Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, Flask CA, Novick AC, Goldfarb DA, Kramer-Zucker A et al (2006) The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci USA 103:5466–5471PubMedPubMedCentralCrossRefGoogle Scholar
  208. Signor D, Wedaman KP, Orozco JT, Dwyer ND, Bargmann CI, Rose LS, Scholey JM (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 147:519–530PubMedPubMedCentralCrossRefGoogle Scholar
  209. Simons M, Gloy J, Ganner A, Bullerkotte A, Bashkurov M, Kronig C, Schermer B, Benzing T, Cabello OA, Jenny A et al (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 37:537–543PubMedPubMedCentralCrossRefGoogle Scholar
  210. Siroky BJ, Ferguson WB, Fuson AL, Xie Y, Fintha A, Komlosi P, Yoder BK, Schwiebert EM, Guay-Woodford LM, Bell PD (2006) Loss of primary cilia results in deregulated and unabated apical calcium entry in ARPKD collecting duct cells. Am J Physiol Renal Physiol 290:F1320–F1328PubMedCrossRefGoogle Scholar
  211. 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 17:2821–2831PubMedCrossRefGoogle Scholar
  212. Song L, Dentler WL (2001) Flagellar protein dynamics in Chlamydomonas. J Biol Chem 276:29754–29763PubMedCrossRefGoogle Scholar
  213. Song X, Di Giovanni V, He N, Wang K, Ingram A, Rosenblum ND, Pei Y (2009) Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks. Hum Mol Genet 18:2328–2343PubMedCrossRefGoogle Scholar
  214. Sorokin S (1962) Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells. J Cell Biol 15:363–377PubMedPubMedCentralCrossRefGoogle Scholar
  215. Spalluto C, Wilson DI, Hearn T (2012) Nek2 localises to the distal portion of the mother centriole/basal body and is required for timely cilium disassembly at the G2/M transition. Eur J Cell Biol 91:675–686PubMedCrossRefGoogle Scholar
  216. Stephens RE (1997) Synthesis and turnover of embryonic sea urchin ciliary proteins during selective inhibition of tubulin synthesis and assembly. Mol Biol Cell 8:2187–2198PubMedPubMedCentralCrossRefGoogle Scholar
  217. Stottmann RW, Tran PV, Turbe-Doan A, Beier DR (2009) Ttc21b is required to restrict sonic hedgehog activity in the developing mouse forebrain. Dev Biol 335:166–178PubMedPubMedCentralCrossRefGoogle Scholar
  218. Su X, Driscoll K, Yao G, Raed A, Wu M, Beales PL, Zhou J (2014) Bardet–Biedl syndrome proteins 1 and 3 regulate the ciliary trafficking of polycystic kidney disease 1 protein. Hum Mol Genet 23:5441–5451PubMedPubMedCentralCrossRefGoogle Scholar
  219. Su S, Phua SC, DeRose R, Chiba S, Narita K, Kalugin PN, Katada T, Kontani K, Takeda S, Inoue T (2013) Genetically encoded calcium indicator illuminates calcium dynamics in primary cilia. Nat Methods 10:1105–1107PubMedCrossRefGoogle Scholar
  220. Su X, Wu M, Yao G, El-Jouni W, Luo C, Tabari A, Zhou J (2015) Regulation of polycystin-1 ciliary trafficking by motifs at its C-terminus and polycystin-2 but not by cleavage at the GPS site. J Cell Sci 128:4063–4073PubMedPubMedCentralCrossRefGoogle Scholar
  221. Sugiyama N, Tsukiyama T, Yamaguchi TP, Yokoyama T (2011) The canonical Wnt signaling pathway is not involved in renal cyst development in the kidneys of inv mutant mice. Kidney Int 79:957–965PubMedCrossRefGoogle Scholar
  222. Sun Z, Amsterdam A, Pazour GJ, Cole DG, Miller MS, Hopkins N (2004) A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney. Development 131:4085–4093PubMedPubMedCentralCrossRefGoogle Scholar
  223. Takakura A, Nelson EA, Haque N, Humphreys BD, Zandi-Nejad K, Frank DA, Zhou J (2011) Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum Mol Genet 20:4143–4154PubMedPubMedCentralCrossRefGoogle Scholar
  224. Takiar V, Nishio S, Seo-Mayer P, King JD Jr, Li H, Zhang L, Karihaloo A, Hallows KR, Somlo S, Caplan MJ (2011) Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci USA 108:2462–2467PubMedPubMedCentralCrossRefGoogle Scholar
  225. Talbot JJ, Shillingford JM, Vasanth S, Doerr N, Mukherjee S, Kinter MT, Watnick T, Weimbs T (2011) Polycystin-1 regulates STAT activity by a dual mechanism. Proc Natl Acad Sci USA 108:7985–7990PubMedPubMedCentralCrossRefGoogle Scholar
  226. Talbot JJ, Song X, Wang X, Rinschen MM, Doerr N, LaRiviere WB, Schermer B, Pei YP, Torres VE, Weimbs T (2014) The cleaved cytoplasmic tail of polycystin-1 regulates Src-dependent STAT3 activation. J Am Soc Nephrol 25:1737–1748PubMedPubMedCentralCrossRefGoogle Scholar
  227. Tam LW, Ranum PT, Lefebvre PA (2013) CDKL5 regulates flagellar length and localizes to the base of the flagella in Chlamydomonas. Mol Biol Cell 24:588–600PubMedPubMedCentralCrossRefGoogle Scholar
  228. Tam LW, Wilson NF, Lefebvre PA (2007) A CDK-related kinase regulates the length and assembly of flagella in Chlamydomonas. J Cell Biol 176:819–829PubMedPubMedCentralCrossRefGoogle Scholar
  229. Tao S, Kakade VR, Woodgett JR, Pandey P, Suderman ED, Rajagopal M, Rao R (2015) Glycogen synthase kinase-3beta promotes cyst expansion in polycystic kidney disease. Kidney Int 87:1164–1175PubMedPubMedCentralCrossRefGoogle Scholar
  230. Tao Y, Kim J, Schrier RW, Edelstein CL (2005) Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol 16:46–51PubMedCrossRefGoogle Scholar
  231. Thiel C, Kessler K, Giessl A, Dimmler A, Shalev SA, von der Haar S, Zenker M, Zahnleiter D, Stoss H, Beinder E et al (2011) NEK1 mutations cause short-rib polydactyly syndrome type majewski. Am J Hum Genet 88:106–114PubMedPubMedCentralCrossRefGoogle Scholar
  232. Thompson CL, Chapple JP, Knight MM (2014) Primary cilia disassembly down-regulates mechanosensitive hedgehog signalling: a feedback mechanism controlling ADAMTS-5 expression in chondrocytes. Osteoarthr Cartil 22:490–498PubMedPubMedCentralCrossRefGoogle Scholar
  233. Torres VE, Harris PC (2006) Mechanisms of disease: autosomal dominant and recessive polycystic kidney diseases. Nat Clin Pract Nephrol 2:40–55 quiz 55PubMedCrossRefGoogle Scholar
  234. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS (2012) Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 367:2407–2418PubMedPubMedCentralCrossRefGoogle Scholar
  235. Torres VE, Meijer E, Bae KT, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB et al (2011) Rationale and design of the TEMPO (tolvaptan efficacy and safety in management of autosomal dominant polycystic kidney disease and its outcomes) 3–4 study. Am J Kidney Dis 57:692–699PubMedCrossRefGoogle Scholar
  236. Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH 2nd (2004) Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med 10:363–364PubMedCrossRefGoogle Scholar
  237. Tran PV, Lechtreck KF (2016) An age of enlightenment for cilia: the FASEB summer research conference on the “Biology of cilia and flagella”. Dev Biol 409:319–328PubMedCrossRefGoogle Scholar
  238. Tran PV, Sharma M, Li X, Calvet JP (2014a) Developmental signaling: does it bridge the gap between cilia dysfunction and renal cystogenesis? Birth Defects Res C Embryo Today 102:159–173PubMedPubMedCentralCrossRefGoogle Scholar
  239. Tran PV, Talbott GC, Turbe-Doan A, Jacobs DT, Schonfeld MP, Silva LM, Chatterjee A, Prysak M, Allard BA, Beier DR (2014b) Downregulating Hedgehog signaling reduces renal cystogenic potential of mouse models. J Am Soc Nephrol 25(10):2201–2212. doi: 10.1681/ASN.2013070735. Epub 2014 Apr 3CrossRefPubMedPubMedCentralGoogle Scholar
  240. Tran PV, Haycraft CJ, Besschetnova TY, Turbe-Doan A, Stottmann RW, Herron BJ, Chesebro AL, Qiu H, Scherz PJ, Shah JV et al (2008) THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet 40:403–410PubMedPubMedCentralCrossRefGoogle Scholar
  241. Tran U, Zakin L, Schweickert A, Agrawal R, Doger R, Blum M, De Robertis EM, Wessely O (2010) The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity. Development 137:1107–1116PubMedPubMedCentralCrossRefGoogle Scholar
  242. Trudel M, Yao Q, Qian F (2016) The role of G-protein-coupled receptor proteolysis site cleavage of polycystin-1 in renal physiology and polycystic kidney disease. Cells 5Google Scholar
  243. Upadhyay VS, Muntean BS, Kathem SH, Hwang JJ, Aboualaiwi WA, Nauli SM (2014) Roles of dopamine receptor on chemosensory and mechanosensory primary cilia in renal epithelial cells. Front Physiol 5:72PubMedPubMedCentralCrossRefGoogle Scholar
  244. van der Vaart A, Rademakers S, Jansen G (2015) DLK-1/p38 MAP kinase signaling controls cilium length by regulating RAB-5 mediated endocytosis in Caenorhabditis elegans. PLoS Genet 11:e1005733PubMedPubMedCentralCrossRefGoogle Scholar
  245. Verghese E, Ricardo SD, Weidenfeld R, Zhuang J, Hill PA, Langham RG, Deane JA (2009) Renal primary cilia lengthen after acute tubular necrosis. J Am Soc Nephrol 20:2147–2153PubMedPubMedCentralCrossRefGoogle Scholar
  246. Verghese E, Weidenfeld R, Bertram JF, Ricardo SD, Deane JA (2008) Renal cilia display length alterations following tubular injury and are present early in epithelial repair. Nephrol Dial Transplant 23:834–841PubMedCrossRefGoogle Scholar
  247. Wahl PR, Serra AL, Le Hir M, Molle KD, Hall MN, Wuthrich RP (2006) Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant 21:598–604PubMedCrossRefGoogle Scholar
  248. Walczak-Sztulpa J, Eggenschwiler J, Osborn D, Brown DA, Emma F, Klingenberg C, Hennekam RC, Torre G, Garshasbi M, Tzschach A et al (2010) Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. Am J Hum Genet 86:949–956PubMedPubMedCentralCrossRefGoogle Scholar
  249. Wallace DP (2011) Cyclic AMP-mediated cyst expansion. Biochim Biophys Acta 1812:1291–1300PubMedCrossRefGoogle Scholar
  250. Walz G, Budde K, Mannaa M, Nurnberger J, Wanner C, Sommerer C, Kunzendorf U, Banas B, Horl WH, Obermuller N et al (2010) Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 363:830–840PubMedCrossRefGoogle Scholar
  251. Wang X, Gattone V 2nd, Harris PC, Torres VE (2005) Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. J Am Soc Nephrol 16:846–851PubMedCrossRefGoogle Scholar
  252. Wang W, Li F, Sun Y, Lei L, Zhou H, Lei T, Xia Y, Verkman AS, Yang B (2015) Aquaporin-1 retards renal cyst development in polycystic kidney disease by inhibition of Wnt signaling. FASEB J 29:1551–1563PubMedPubMedCentralCrossRefGoogle Scholar
  253. Wang J, Silva M, Haas LA, Morsci NS, Nguyen KC, Hall DH, Barr MM (2014) C. elegans ciliated sensory neurons release extracellular vesicles that function in animal communication. Curr Biol 24:519–525PubMedPubMedCentralCrossRefGoogle Scholar
  254. Wang X, Wu Y, Ward CJ, Harris PC, Torres VE (2008) Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol 19:102–108PubMedPubMedCentralCrossRefGoogle Scholar
  255. Wang S, Zhang J, Nauli SM, Li X, Starremans PG, Luo Y, Roberts KA, Zhou J (2007) Fibrocystin/polyductin, found in the same protein complex with polycystin-2, regulates calcium responses in kidney epithelia. Mol Cell Biol 27:3241–3252PubMedPubMedCentralCrossRefGoogle Scholar
  256. Ward HH, Brown-Glaberman U, Wang J, Morita Y, Alper SL, Bedrick EJ, Gattone VH 2nd, Deretic D, Wandinger-Ness A (2011) A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1. Mol Biol Cell 22:3289–3305PubMedPubMedCentralCrossRefGoogle Scholar
  257. Wei W, Hackmann K, Xu H, Germino G, Qian F (2007) Characterization of cis-autoproteolysis of polycystin-1, the product of human polycystic kidney disease 1 gene. J Biol Chem 282:21729–21737PubMedCrossRefGoogle Scholar
  258. Weimbs T (2007) Polycystic kidney disease and renal injury repair: common pathways, fluid flow, and the function of polycystin-1. Am J Physiol Renal Physiol 293:F1423–F1432PubMedCrossRefGoogle Scholar
  259. Westlake CJ, Baye LM, Nachury MV, Wright KJ, Ervin KE, Phu L, Chalouni C, Beck JS, Kirkpatrick DS, Slusarski DC et al (2011) Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome. Proc Natl Acad Sci USA 108:2759–2764PubMedPubMedCentralCrossRefGoogle Scholar
  260. Wheway G, Abdelhamed Z, Natarajan S, Toomes C, Inglehearn C, Johnson CA (2013) Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel–Gruber syndrome. Dev Biol 377:55–66PubMedCrossRefGoogle Scholar
  261. White MC, Quarmby LM (2008) The NIMA-family kinase, Nek1 affects the stability of centrosomes and ciliogenesis. BMC Cell Biol 9:29PubMedPubMedCentralCrossRefGoogle Scholar
  262. Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, Bialas NJ, Stupay RM, Chen N, Blacque OE 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 192:1023–1041PubMedPubMedCentralCrossRefGoogle Scholar
  263. Wloga D, Camba A, Rogowski K, Manning G, Jerka-Dziadosz M, Gaertig J (2006) Members of the NIMA-related kinase family promote disassembly of cilia by multiple mechanisms. Mol Biol Cell 17:2799–2810PubMedPubMedCentralCrossRefGoogle Scholar
  264. Wood CR, Rosenbaum JL (2015) Ciliary ectosomes: transmissions from the cell’s antenna. Trends Cell Biol 25:276–285PubMedPubMedCentralCrossRefGoogle Scholar
  265. Wood CR, Huang K, Diener DR, Rosenbaum JL (2013) The cilium secretes bioactive ectosomes. Curr Biol 23:906–911PubMedCrossRefGoogle Scholar
  266. Woollard JR, Punyashtiti R, Richardson S, Masyuk TV, Whelan S, Huang BQ, Lager DJ, vanDeursen J, Torres VE, Gattone VH et al (2007) A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation. Kidney Int 72:328–336PubMedCrossRefGoogle Scholar
  267. Wright KJ, Baye LM, Olivier-Mason A, Mukhopadhyay S, Sang L, Kwong M, Wang W, Pretorius PR, Sheffield VC, Sengupta P et al (2011) An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium. Genes Dev 25:2347–2360PubMedPubMedCentralCrossRefGoogle Scholar
  268. Xu Q, Zhang Y, Wei Q, Huang Y, Li Y, Ling K, Hu J (2015) BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors. Sci Rep 5:11855PubMedPubMedCentralCrossRefGoogle Scholar
  269. 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 17:178–187PubMedCrossRefGoogle Scholar
  270. Yamaguchi T, Nagao S, Kasahara M, Takahashi H, Grantham JJ (1997) Renal accumulation and excretion of cyclic adenosine monophosphate in a murine model of slowly progressive polycystic kidney disease. Am J Kidney Dis 30:703–709PubMedCrossRefGoogle Scholar
  271. Yamaguchi T, Wallace DP, Magenheimer BS, Hempson SJ, Grantham JJ, Calvet JP (2004) Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J Biol Chem 279:40419–40430PubMedCrossRefGoogle Scholar
  272. Yang TT, Su J, Wang WJ, Craige B, Witman GB, Tsou MF, Liao JC (2015) Superresolution pattern recognition reveals the architectural map of the ciliary transition zone. Sci Rep 5:14096PubMedCrossRefGoogle Scholar
  273. Ye H, Wang X, Sussman CR, Hopp K, Irazabal MV, Bakeberg JL, LaRiviere WB, Manganiello VC, Vorhees CV, Zhao H et al (2015) Modulation of polycystic kidney disease severity by phosphodiesterase 1 and 3 subfamilies. J Am Soc Nephrol 27(5):1312–1320. doi: 10.1681/ASN.2015010057. Epub 2015 Sep 15CrossRefPubMedPubMedCentralGoogle Scholar
  274. Ying G, Avasthi P, Irwin M, Gerstner CD, Frederick JM, Lucero MT, Baehr W (2014) Centrin 2 is required for mouse olfactory ciliary trafficking and development of ependymal cilia planar polarity. J Neurosci 34:6377–6388PubMedPubMedCentralCrossRefGoogle Scholar
  275. Yoder BK, Hou X, Guay-Woodford LM (2002) The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13:2508–2516PubMedCrossRefGoogle Scholar
  276. Young RW (1971) The renewal of rod and cone outer segments in the rhesus monkey. J Cell Biol 49:303–318PubMedPubMedCentralCrossRefGoogle Scholar
  277. Young RW, Bok D (1969) Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol 42:392–403PubMedPubMedCentralCrossRefGoogle Scholar
  278. Yuan S, Zhao L, Brueckner M, Sun Z (2015) Intraciliary calcium oscillations initiate vertebrate left–right asymmetry. Curr Biol 25:556–567PubMedPubMedCentralCrossRefGoogle Scholar
  279. Zaika O, Mamenko M, Berrout J, Boukelmoune N, O’Neil RG, Pochynyuk O (2013) TRPV4 dysfunction promotes renal cystogenesis in autosomal recessive polycystic kidney disease. J Am Soc Nephrol 24:604–616PubMedPubMedCentralCrossRefGoogle Scholar
  280. Zhang ZR, Chu WF, Song B, Gooz M, Zhang JN, Yu CJ, Jiang S, Baldys A, Gooz P, Steele S et al (2013) TRPP2 and TRPV4 form an EGF-activated calcium permeable channel at the apical membrane of renal collecting duct cells. PLoS One 8:e73424PubMedPubMedCentralCrossRefGoogle Scholar
  281. Zhang Q, Nishimura D, Seo S, Vogel T, Morgan DA, Searby C, Bugge K, Stone EM, Rahmouni K, Sheffield VC (2011) Bardet–Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes. Proc Natl Acad Sci USA 108:20678–20683PubMedPubMedCentralCrossRefGoogle Scholar
  282. Zhang Q, Yu D, Seo S, Stone EM, Sheffield VC (2012) Intrinsic protein–protein interaction-mediated and chaperonin-assisted sequential assembly of stable Bardet–Biedl syndrome protein complex, the BBSome. J Biol Chem 287:20625–20635PubMedPubMedCentralCrossRefGoogle Scholar
  283. Zhou J (2009) Polycystins and primary cilia: primers for cell cycle progression. Annu Rev Physiol 71:83–113PubMedCrossRefGoogle Scholar
  284. Zimmermann KW (1898) Beitrage zur Kenntniss einiger Drusen und Epithelien. Arch Mikrosk Anat 52:552–706CrossRefGoogle Scholar
  285. Zuo X, Fogelgren B, Lipschutz JH (2011) The small GTPase Cdc42 is necessary for primary ciliogenesis in renal tubular epithelial cells. J Biol Chem 286:22469–22477PubMedPubMedCentralCrossRefGoogle Scholar
  286. Zuo X, Guo W, Lipschutz JH (2009) The exocyst protein Sec10 is necessary for primary ciliogenesis and cystogenesis in vitro. Mol Biol Cell 20:2522–2529PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer International Publishing AG 2017

Open Access This chapter is distributed under the terms of the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Authors and Affiliations

  • Prachee Avasthi
    • 1
  • Robin L. Maser
    • 2
    • 3
  • Pamela V. Tran
    • 1
    • 3
  1. 1.Department of Anatomy and Cell BiologyUniversity of Kansas Medical CenterKansas CityUSA
  2. 2.Department of Clinical Laboratory SciencesUniversity of Kansas Medical CenterKansas CityUSA
  3. 3.Kidney InstituteUniversity of Kansas Medical CenterKansas CityUSA

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