Keeping the balance between proliferation and differentiation: The primary cilium

Current Genomics

Volumn 12, Issue 4, 2011, Pages 285-297

  Irigoín, Florencia ^a,b   Badano, Jose L ^a  

^a UNIVERSIDAD DE LA REPÚBLICA   (Uruguay)

^b DEPARTAMENTO DE BIOQUÍMICA   (Uruguay)

Author keywords

Cancer; Cell cycle; Cilia; Ciliopathies

Indexed keywords

PLATELET DERIVED GROWTH FACTOR ALPHA RECEPTOR; POLYCYSTIN; SONIC HEDGEHOG PROTEIN; WNT PROTEIN;

ARTICLE; BIOGENESIS; CELL CYCLE; CELL DIFFERENTIATION; CELL FATE; CELL PROLIFERATION; EUKARYOTIC FLAGELLUM; HUMAN; NEOPLASM; NONHUMAN; PARACRINE SIGNALING; PHENOTYPE; SIGNAL TRANSDUCTION;

EID: 79959991643     PISSN: 13892029     EISSN: 18755488     Source Type: Journal    
DOI: 10.2174/138920211795860134     Document Type: Article

References (128)

1. Rosenbaum, J.L.; Witman, G.B. Intraflagellar transport. Nat. Rev. Mol. Cell Biol., 2002, 3, 813-825.
2. Cardenas-Rodriguez, M.; Badano, J.L. Ciliary biology: understanding the cellular and genetic basis of human ciliopathies. Am. J. Med. Genet. C Semin. Med. Genet., 2009, 151C, 263-280.
3. Kozminski, K.G.; Johnson, K.A.; Forscher, P.; Rosenbaum, J.L. A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc. Natl. Acad. Sci. USA, 1993, 90, 5519-5523.
4. Pedersen, L.B.; Rosenbaum, J.L. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr. Top. Dev. Biol., 2008, 85, 23-61.
5. Badano, J.L.; Mitsuma, N.; Beales, P.L.; Katsanis, N. The ciliopathies: An emergin class of human genetic disorders. Annu. Rev. Genomics Hum. Genet., 2006, 7, 125-148.
6. Fliegauf, M.; Benzing, T.; Omran, H. When cilia go bad: cilia defects and ciliopathies. Nat. Rev. Mol. Cell. Biol., 2007, 8, 880- 893.
7. Gerdes, J.M.; Davis, E.E.; Katsanis, N. The vertebrate primary cilium in development, homeostasis, and disease. Cell, 2009, 137, 32-45.
8. Sharma, N.; Berbari, N.F.; Yoder, B.K. Ciliary dysfunction in developmental abnormalities and diseases. Curr. Top. Dev. Biol., 2008, 85, 371-427.
9. Wong, S.Y.; Seol, A.D.; So, P.L.; Ermilov, A.N.; Bichakjian, C.K.; Epstein, E.H.J.; Dlugosz, A.A.; Reiter, J.F. Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis. Nat. Med., 2009, 15, 1055-1061.
10. Christensen, S.T.; Pedersen, S.F.; Satir, P.; Veland, I.R.; Schneider, L. The primary cilium coordinates signaling pathways in cell cycle control and migration during development and tissue repair. Curr. Top. Dev. Biol., 2008, 85, 261-301.
11. Gerdes, J.M.; Katsanis, N. Ciliary function and Wnt signal modulation. Curr. Top. Dev. Biol., 2008, 85, 175-195.
12. Haycraft, C.J.; Banizs, B.; Aydin-Son, Y.; Zhang, Q.; Michaud, E.J.; Yoder, B.K. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet., 2005, 1, 0480-0488.
13. Huangfu, D.; Anderson, K.V. Cilia and Hedgehog responsiveness in the mouse. Proc. Natl. Acad. Sci. USA, 2005, 102, 11325-11330.
14. Huangfu, D.; Liu, A.; Rakeman, A.S.; Murcia, N.S.; Niswander, L.; Anderson, K.V. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature, 2003, 426, 83-87.
15. Debec, A.; Sullivan, W.; Bettencourt-Dias, M. Centrioles: active players or passengers during mitosis? Cell. Mol. Life Sci., 2010, 67, 2173-2194.
16. Hinchcliffe, E.H.; Li, C.; Thompson, E.A.; Maller, J.L.; Sluder, G. Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts. Science, 1999, 283, 851-854.
17. Plotnikova, O.V.; Pugacheva, E.N.; Golemis, E.A. Primary cilia and the cell cycle. Methods Cell Biol., 2009, 94, 137-160.
18. Santos, N.; Reiter, J.F. Building it up and taking it down: the regulation of vertebrate ciliogenesis. Dev. Dyn., 2008, 237, 1972- 1981.
19. Rieder, C.L.; Jensen, C.G.; Jensen, L.C. The resorption of primary cilia during mitosis in a vertebrate (PtK1) cell line. J. Ultrastruct. Res., 1979, 68, 173-185.
20. Basto, R.; Lau, J.; Vinogradova, T.; Gardiol, A.; Woods, C.G.; Khodjakov, A.; Raff, J.W. Flies without centrioles. Cell, 2006, 125, 1375-1386.
21. Bettencourt-Dias, M.; Rodrigues-Martins, A.; Carpenter, L.; Riparbelli, M.; Lehmann, L.; Gatt, M.K.; Carmo, N.; Balloux, F.; Callaini, G.; Glover, D.M. SAK/PLK4 is required for centriole duplication and flagella development. Curr. Biol., 2005, 15, 2199-2207.
22. Habedanck, R.; Stierhof, Y.D.; Wilkinson, C.J.; Nigg, E.A. The Polo kinase Plk4 functions in centriole duplication. Nat. Cell Biol., 2005, 7, 1140-1146.
23. Uetake, Y.; Loncarek, J.; Nordberg, J.J.; English, C.N.; La Terra, S.; Khodjakov, A.; Sluder, G. Cell cycle progression and de novo centriole assembly after centrosomal removal in untransformed human cells. J. Cell Biol., 2007, 176, 173-182.
24. Chen, Z.; Indjeian, V.B.; McManus, M.; Wang, L.; Dynlacht, B.D. CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. Dev. Cell, 2002, 3, 339-350.
25. Spektor, A.; Tsang, W.Y.; Khoo, D.; Dynlacht, B.D. Cep97 and CP110 suppress a cilia assembly program. Cell, 2007, 130, 678-690.
26. Tsang, W.Y.; Bossard, C.; Khanna, H.; Peränen, J.; Swaroop, A.; Malhotra, V.; Dynlacht, B.D. CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease. Dev. Cell, 2008, 15, 187-197.
27. Pugacheva, E.N.; Jablonski, S.A.; Hartman, T.R.; Henske, E.P.; Golemis, E.A. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell, 2007, 129, 1351-1363.
28. Bradley, B.A.; Quarmby, L.M. A NIMA-related kinase, Cnk2p, regulates both flagellar length and cell size in Chlamydomonas. J. Cell Sci., 2005, 118, 3317-3326.
29. Mahjoub, M.R.; Montpetit, B.; Zhao, L.; Finst, R.J.; Goh, B.; Kim, A.C.; Quarmby, L.M. The FA2 gene of Chlamydomonas encodes a NIMA family kinase with roles in cell cycle progression and microtubule severing during deflagellation. J. Cell Sci., 2002, 115, 1759-1768.
30. Wloga, D.; Camba, A.; Rogowski, K.; Manning, G.; Jerka- Dziadosz, M.; Gaertig, J. Members of the NIMA-related kinase family promote disassembly of cilia by multiple mechanisms. Mol. Biol. Cell, 2006, 17, 2799-2810.
31. Tan, B.C.; Lee, S.C. Nek9, a novel FACT-associated protein, modulates interphase progression. J. Biol. Chem., 2004, 279, 9321-9330.
32. Yin, M.J.; Shao, L.; Voehringer, D.; Smeal, T.; Jallal, B. The serine/threonine kinase Nek6 is required for cell cycle progression through mitosis. J. Biol. Chem., 2003, 278, 52454-52460.
33. Yissachar, N.; Salem, H.; Tennenbaum, T.; Motro, B. Nek7 kinase is enriched at the centrosome, and is required for proper spindle assembly and mitotic progression. FEBS Lett., 2006, 580, 6489-6495.
34. Liu, S.; Lu, W.; Obara, T.; Kuida, S.; Lehoczky, J.; Dewar, K.; Drummond, I.A.; Beier, D.R. A defect in a novel Nek-family kinase causes cystic kidney disease in the mouse and in zebrafish. Development, 2002, 129, 5839-5846.
35. Upadhya, P.; Birkenmeier, E.H.; Birkenmeier, C.S.; Barker, J.E. Mutations in a NIMA-related kinase gene, Nek1, cause pleiotropic effects including a progressive polycystic kidney disease in mice. Proc. Natl. Acad. Sci. USA, 2000, 97, 217-221.
36. Shalom, O.; Shalva, N.; Altschuler, Y.; Motro, B. The mammalian Nek1 kinase is involved in primary cilium formation. FEBS Lett., 2008, 582, 1465-1470.
37. White, M.C.; Quarmby, L.M. The NIMA-family kinase, Nek1 affects the stability of centrosomes and ciliogenesis. BMC Cell Biol., 2008, 4, 9-29.
38. Hilton, L.K.; White, M.C.; Quarmby, L.M. The NIMA-related kinase NEK1 cycles through the nucleus. Biochem. Biophys. Res. Commun., 2009, 389, 52-56.
39. Mahjoub, M.R.; Trapp, M.L.; Quarmby, L.M. NIMA-related kinases defective in murine models of polycystic kidney diseases localize to primary cilia and centrosomes. J. Am. Soc. Nephrol., 2005, 16, 3485-3489.
40. Otto, E.A.; Trapp, M.L.; Schultheiss, U.T.; Helou, J.; Quarmby, L.M.; Hildebrandt, F. NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis. J. Am. Soc. Nephrol., 2008, 19, 587-592.
41. Smith, L.A.; Bukanov, N.O.; Husson, H.; Russo, R.J.; Barry, T.C.; Taylor, A.L.; Beier, D.R.; Ibraghimov-Beskrovnaya, O. 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., 2006, 17, 2821-2831.
42. Parker, J.D.; Bradley, B.A.; Mooers, A.O.; Quarmby, L.M. Phylogenetic analysis of the Neks reveals early diversification of ciliary-cell cycle kinases. PloS ONE, 2007, 2, e1076.
43. Quarmby, L.M.; Mahjoub, M.R. Caught Nek-ing: cilia and centrioles. J. Cell Sci., 2005, 118, 5161-5169.
44. Jurczyk, A.; Gromley, A.; Redick, S.; San Agustin, J.; Witman, G.; Pazour, G.J.; Peters, D.J.; Doxsey, S. Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly. J. Cell Biol., 2004, 166, 637-643.
45. Patzke, S.; Redick, S.; Warsame, A.; Murga-Zamalloa, C.A.; Khanna, H.; Doxsey, S.; Stokke, T. CSPP is a ciliary protein interacting with Nephrocystin 8 and required for cilia formation. Mol. Biol. Cell, 2010, 21, 2555-2567.
46. Pazour, G.J.; Dickert, B.L.; Vucica, Y.; Seeley, E.S.; Rosenbaum, J.L.; Witman, G.B.; Cole, D.G. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J. Cell Biol., 2000, 151, 709-718.
47. Moyer, J.H.; Lee-Tischler, M.J.; Kwon, H.Y.; Schrick, J.J.; Avner, E.D.; Sweeney, W.E.; Godfrey, V.L.; Cacheiro, N.L.; Wilkinson, J.E.; Woychik, R.P. Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice. Science, 1994, 264, 1329-1333.
48. Yoder, B.K.; Richards, W.G.; Sweeney, W.E.; Wilkinson, J.E.; Avener, E.D.; Woychik, R.P. Insertional mutagenesis and molecular analysis of a new gene associated with polycystic kidney disease. Proc. Assoc. Am. Physicians, 1995, 107, 314-323.
49. Taulman, P.D.; Haycraft, C.J.; Balkovetz, D.F.; Yoder, B.K. Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia. Mol. Biol. Cell, 2001, 12, 589-599.
50. Robert, A.; Margall-Ducos, G.; Guidotti, J.E.; Brégerie, O.; Celati, C.; Bréchot, C.; Desdouets, C. The intraflagellar transport component IFT88/polaris is a centrosomal protein regulating G1-S transition in non-ciliated cells. J. Cell Sci., 2007, 120, 628-637.
51. Fanciulli, M.; Bruno, T.; Di Padova, M.; De Angelis, R.; Iezzi, S.; Iacobini, C.; Floridi, A.; Passananti, C. Identification of a novel partner of RNA polymerase II subunit 11, Che-1, which interacts with and affects the growth suppression function of Rb. FASEB J., 2000, 14, 904-912.
52. Giorgio, G.; Alfieri, M.; Prattichizzo, C.; Zullo, A.; Cairo, S.; Franco, B. Functional characterization of the OFD1 protein reveals a nuclear localization and physical interaction with subunits of a chromatin remodeling complex. Mol. Biol. Cell, 2007, 18, 4397-4404.
53. Qin, H.; Wang, Z.; Diener, D.; Rosenbaum, J. Intraflagellar transport protein 27 is a small G protein involved in cell-cycle control. Curr. Biol., 2007, 17, 193-202.
54. Jonassen, J.A.; San Agustin, J.; Follit, J.A.; Pazour, G.J. Deletion of IFT20 in the mouse kidney causes misorientation of the mitotic spindle and cystic kidney disease. J. Cell Biol., 2008, 183, 377-384.
55. Zhou, J. Polycystins and primary cilia: primers for cell cycle progression. Annu. Rev. Physiol., 2009, 71, 83-113.
56. Consortium, T.E.P.K.D. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell, 1994, 77, 881-894.
57. Mochizuki, T.; Wu, G.; Hayashi, T.; Xenophontos, S.; Veldhuisen, B.; Saris, J.; Renolds, D.; Cai, Y.; Gabow, P.; Pierides, A.; Kimberling, W.; Breuning, M.; Deltas, C.; Peters, D.; Somlo, S. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science, 1996, 272, 1339-1342.
58. Consortium, T.I.P.K.D. Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. The International Polycystic Kidney Disease Consortium. Cell, 1995, 81, 289-298.
59. Delmas, P.; Nomura, H.; Li, X.; Lakkis, M.; Luo, Y.; Segal, Y.; Fernandez-Fernandez, J.M.; Harris, P.; Frischauf, A.M.; Brown, D.A.; Zhou, J. Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2. J. Biol. Chem., 2002, 277, 11276-11283.
60. Parnell, S.C.; Magenheimer, B.S.; Maser, R.L.; Zien, C.A.; Frischauf, A.M.; Calvet, J.P. Polycystin-1 activation of c-Jun Nterminal kinase and AP-1 is mediated by heterotrimeric G proteins. J. Biol. Chem., 2002, 277, 19566-19572.
61. Gonzalez-Perrett, S.; Kim, K.; Ibarra, C.; Damiano, A.E.; Zotta, E.; Batelli, M.; Harris, P.C.; Reisin, I.L.; Arnaout, M.A.; Cantiello, H.F. Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel. Proc. Natl. Acad. Sci. USA, 2001, 98, 1182-1187.
62. Pazour, G.J.; San Agustin, J.T.; Follit, J.A.; Rosenbaum, J.L.; Witman, G.B. Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in ORPK mice with polycystic kidney disease. Curr. Biol., 2002, 12, R378-R380.
63. Qian, F.; Germino, F.J.; Cai, Y.; Zhang, X.; Somlo, S.; Germino, G.G. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat. Genet., 1997, 16, 179-183.
64. Tsiokas, L.; Kim, E.; Arnould, T.; Sukhatme, V.P.; Walz, G. Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proc. Natl. Acad. Sci. USA, 1997, 94, 6965-6970.
65. Yoder, B.K.; Hou, X.; Guay-Woodford, L.M. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J. Am. Soc. Nephrol., 2002, 13, 2508-2516.
66. Delmas, P. Polycystins: from mechanosensation to gene regulation. Cell, 2004, 118, 145-148.
67. Gascue, C.; Katsanis, N.; Badano, J.L. Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms. Pediatr. Nephrol., 2010, DOI 10.1007/s00467-010-1697-5.
68. Boletta, A.; Qian, F.; Onuchic, L.F.; Bhunia, A.K.; Phakdeekitcharoen, B.; Hanaoka, K.; Guggino, W.; Monaco, L.; Germino, G.G. Polycystin-1, the gene product of PKD1, induces resistance to apoptosis and spontaneous tubulogenesis in MDCK cells. Mol. Cell, 2000, 6, 1267-1273.
69. Bhunia, A.K.; Piontek, K.; Boletta, A.; Liu, L.; Qian, F.; Xu, P.N.; Germino, F.J.; Germino, G.G. PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell, 2002, 109, 157-168.
70. Li, X.; Luo, Y.; Starremans, P.G.; McNamara, C.A.; Pei, Y.; Zhou, J. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat. Cell Biol, 2005, 7, 1202-1212.
71. Peverali, F.A.; Ramqvist, T.; Saffrich, R.; Pepperkok, R.; Barone, M.V.; Philipson, L. Regulation of G1 progression by E2A and Id helix-loop-helix proteins. Embo J., 1994, 13, 4291-4301.
72. Prabhu, S.; Ignatova, A.; Park, S.T.; Sun, X.H. Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins. Mol. Cell Biol., 1997, 17, 5888-5896.
73. Praetorius, H.A.; Spring, K.R. Bending the MDCK cell primary cilium increases intracellular calcium. J. Membr. Biol., 2001, 184, 71-79.
74. Hanaoka, K.; Qian, F.; Boletta, A.; Bhunia, A.K.; Piontek, K.; Tsiokas, L.; Sukhatme, V.P.; Guggino, W.B.; Germino, G.G. Coassembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature, 2000, 408, 990-994.
75. Nauli, S.M.; Alenghat, F.J.; Luo, Y.; Williams, E.; Vassilev, P.; Li, X.; Elia, A.E.; Lu, W.; Brown, E.M.; Quinn, S.J.; Ingber, D.E.; Zhou, J. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet., 2003, 33, 129-137.
76. Corbit, K.C.; Aanstad, P.; Singla, V.; Norman, A.R.; Stainier, D.Y.; Reiter, J.F. Vertebrate Smoothened functions at the primary cilium. Nature, 2005, 437, 1018-1021.
77. Handel, M.; Schulz, S.; Stanarius, A.; Schreff, M.; Erdtmann- Vourliotis, M.; Schmidt, H.; Wolf, G.; Hollt, V. Selective targeting of somatostatin receptor 3 to neuronal cilia. Neuroscience, 1999, 89, 909-926.
78. DeWire, S.M.; Ahn, S.; Lefkowitz, R.J.; Shenoy, S.K. Betaarrestins and cell signaling. Annu. Rev. Physiol., 2007, 69, 483-510.
79. Moore, C.A.; Milano, S.K.; Benovic, J.L. Regulation of receptor trafficking by GRKs and arrestins. Annu. Rev. Physiol., 2007, 69, 451-482.
80. Molla-Herman, A.; Boularan, C.; Ghossoub, R.; Scott, M.G.; Burtey, A.; Zarka, M.; Saunier, S.; Concordet, J.P.; Marullo, S.; Benmerah, A. Targeting of beta-arrestin2 to the centrosome and primary cilium: role in cell proliferation control. PLoS One, 2008, 3, e3728.
81. Hu, Q.; Milenkovic, L.; Jin, H.; Scott, M.P.; Nachury, M.V.; Spiliotis, E.T.; Nelson, W.J. A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution. Science, 2010, 329, 436-439.
82. Varjosalo, M.; Taipale, J. Hedgehog: functions and mechanisms. Genes Dev., 2008, 22, 2454-2472.
83. Kovacs, J.J.; Whalen, E.J.; Liu, R.; Xiao, K.; Kim, J.; Chen, M.; Wang, J.; Chen, W.; Lefkowitz, R.J. Beta-arrestin-mediated localization of smoothened to the primary cilium. Science, 2008, 320, 1777-1781.
84. Rohatgi, R.; Milenkovic, L.; Scott, M.P. Patched1 regulates hedgehog signaling at the primary cilium. Science, 2007, 317, 372-376.
85. Liu, A.; Wang, B.; Niswander, L.A. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development, 2005, 132, 3103-3111.
86. Aanstad, P.; Santos, N.; Corbit, K.C.; Scherz, P.J.; Trinh, L.A.; Salvenmoser, W.; Huisken, J.; Reiter, J.F.; Stainier, D.Y. The Extracellular Domain of Smoothened Regulates Ciliary Localization and Is Required for High-Level Hh Signaling. Curr. Biol., 2009, 19, 1034-1039.
87. Stottmann, R.W.; Tran, P.V.; Turbe-Doan, A.; Beier, D.R. Ttc21b is required to restrict sonic hedgehog activity in the developing mouse forebrain. Dev. Biol., 2009, 335, 166-178.
88. Tran, P.V.; Haycraft, C.J.; Besschetnova, T.Y.; Turbe-Doan, A.; Stottmann, R.W.; Herron, B.J.; Chesebro, A.L.; Qiu, H.; Scherz, P.J.; Shah, J.V.; Yoder, B.K.; Beier, D.R. THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat. Genet., 2008, 40, 403-410.
89. Qin, J.; Lin, Y.; Norman, R.X.; Ko, H.W.; Eggenschwiler, J.T. Intraflagellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components. Proc. Natl. Acad. Sci. USA, 2011, 108, 1456-1461.
90. Ocbina, P.J.; Anderson, K.V. Intraflagellar transport, cilia, and mammalian Hedgehog signaling: analysis in mouse embryonic fibroblasts. Dev. Dyn., 2008, 237, 2030-2038.
91. Rix, S.; Calmont, A.; Scambler, P.J.; Beales, P.L. An Ift80 mouse model of short rib polydactyly syndromes shows defects in hedgehog signalling without loss or malformation of cilia. Hum. Mol. Genet., 2011, 20, 1306-1314.
92. St-Jacques, B.; Hammerschmidt, M.; McMahon, A.P. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev., 1999, 13, 2072-2086.
93. Haycraft, C.J.; Zhang, Q.; Song, B.; Jackson, W.S.; Detloff, P.J.; Serra, R.; Yoder, B.K. Intraflagellar transport is essential for endochondral bone formation. Development, 2007, 134, 307-316.
94. Karp, S.J.; Schipani, E.; St-Jacques, B.; Hunzelman, J.; Kronenberg, H.; McMahon, A.P. Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways. Development, 2000, 127, 543-548.
95. Andrae, J.; Gallini, R.; Betsholtz, C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev., 2008, 22, 1276-1312.
96. Schneider, L.; Clement, C.A.; Teilmann, S.C.; Pazour, G.J.; Hoffmann, E.K.; Satir, P.; Christensen, S.T. PDGFRalphaalpha Signaling Is Regulated through the Primary Cilium in Fibroblasts. Curr. Biol., 2005, 15, 1861-1866.
97. Zoncu, R.; Efeyan, A.; Sabatini, D.M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell. Biol., 2011, 12, 21-35.
98. Logan, C.Y.; Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol., 2004, 20, 781-810.
99. Grigoryan, T.; Wend, P.; Klaus, A.; Birchmeier, W. Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev., 2008, 22, 2308-2341
100. Fanto, M.; McNeill, H. Planar polarity from flies to vertebrates. J. Cell Sci., 2004, 117, 527-533.
101. Veeman, M.T.; Axelrod, J.D.; Moon, R.T. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev. Cell, 2003, 5, 367-377.
102. Simons, M.; Gloy, J.; Ganner, A.; Bullerkotte, A.; Bashkurov, M.; Kronig, C.; Schermer, B.; Benzing, T.; Cabello, O.A.; Jenny, A.; Mlodzik, M.; Polok, B.; Driever, W.; Obara, T.; Walz, G. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signalling pathways. Nat. Genet., 2005, 37, 537-543.
103. Ansley, S.J.; Badano, J.L.; Blacque, O.E.; Hill, J.; Hoskins, B.E.; Leitch, C.C.; Kim, J.C.; Ross, A.J.; Eichers, E.R.; Teslovich, T.M.; Mah, A.K.; Johnsen, R.C.; Cavender, J.C.; Lewis, R.A.; Leroux, M.R.; Beales, P.L.; Katsanis, N. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature, 2003, 425, 628-633.
104. Badano, J.L.; Leitch, C.C.; Ansley, S.J.; May-Simera, H.; Lawson, S.; Lewis, R.A.; Beales, P.L.; Dietz, H.C.; Fisher, S.; Katsanis, N. Dissection of epistasis in oligogenic Bardet-Biedl syndrome. Nature, 2006, 439, 326-330.
105. Kim, J.C.; Badano, J.L.; Sibold, S.; Esmail, M.A.; Hill, J.; Hoskins, B.E.; Leitch, C.C.; Venner, K.; Ansley, S.J.; Ross, A.J.; Leroux, M.R.; Katsanis, N.; Beales, P.L. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat. Genet., 2004, 36, 462-470.
106. Kim, J.C.; Ou, Y.Y.; Badano, J.L.; Esmail, M.A.; Leitch, C.C.; Fiedrich, E.; Beales, P.L.; Archibald, J.M.; Katsanis, N.; Rattner, J.B.; Leroux, M.R. MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis. J. Cell Sci., 2005, 118, 1007-1020.
107. Li, J.B.; Gerdes, J.M.; Haycraft, C.J.; Fan, Y.; Teslovich, T.M.; May-Simera, H.; Li, H.; Blacque, O.E.; Li, L.; Leitch, C.C.; Lewis, R.A.; Green, J.S.; Parfrey, P.S.; Leroux, M.R.; Davidson, W.S.; Beales, P.L.; Guay-Woodford, L.M.; Yoder, B.K.; Stormo, G.D.; Katsanis, N.; Dutcher, S.K. Comparative genomic identification of conserved flagellar and basal body proteins that includes a novel gene for Bardet-Biedl syndrome. Cell, 2004, 117, 541-552.
108. Jin, H.; White, S.R.; Shida, T.; Schulz, S.; Aguiar, M.; Gygi, S.P.; Bazan, J.F.; Nachury, M.V. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell, 2010, 141, 1208-1219.
109. Loktev, A.V.; Zhang, Q.; Beck, J.S.; Searby, C.C.; Scheetz, T.E.; Bazan, J.F.; Slusarski, D.C.; Sheffield, V.C.; Jackson, P.K.; Nachury, M.V. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev. Cell, 2008, 15, 854-865.
110. Nachury, M.V.; Loktev, A.V.; Zhang, Q.; Westlake, C.J.; Peränen, J.; Merdes, A.; Slusarski, D.C.; Scheller, R.H.; Bazan, J.F.; Sheffield, V.C.; Jackson, P.K. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell, 2007, 129, 1201-1213.
111. Wiens, C.J.; Tong, Y.; Esmail, M.A.; Oh, E.; Gerdes, J.M.; Wang, J.; Tempel, W.; Rattner, J.B.; Katsanis, N.; Park, H.W.; Leroux, M.R. Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. J. Biol. Chem., 2010, 285, 16218-16230.
112. Gerdes, J.M.; Liu, Y.; Zaghloul, N.A.; Leitch, C.C.; Lawson, S.S.; Kato, M.; Beachy, P.A.; Beales, P.L.; DeMartino, G.N.; Fisher, S.; Badano, J.L.; Katsanis, N. Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nat. Genet., 2007, 39, 1350-1360.
113. Corbit, K.C.; Shyer, A.E.; Dowdle, W.E.; Gaulden, J.; Singla, V.; Chen, M.H.; Chuang, P.T.; Reiter, J.F. Kif3a constrains betacatenin- dependent Wnt signalling through dual ciliary and nonciliary mechanisms. Nat. Cell Biol., 2008, 10, 70-76.
114. Ross, A.J.; May-Simera, H.; Eichers, E.R.; Kai, M.; Hill, J.; Jagger, D.J.; Leitch, C.C.; Chapple, J.P.; Munro, P.M.; Fisher, S.; Tan, P.L.; Phillips, H.M.; Leroux, M.R.; Henderson, D.J.; Murdoch, J.N.; Copp, A.J.; Eliot, M.M.; Lupski, J.R.; Kemp, D.T.; Dollfus, H.; Tada, M.; Katsanis, N.; Forge, A.; Beales, P.L. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat. Genet., 2005, 37, 1135-1140.
115. May-Simera, H.L.; Kai, M.; Hernandez, V.; Osborn, D.P.S.; Tada, M.; Beales, P.L. Bbs8, together with the planar cell polarity protein Vangl2, is required to establish left-right asymmetry in zebrafish. Dev. Biol., 2010, 345, 215-225.
116. Kim, S.K.; Shindo, A.; Park, T.J.; Oh, E.C.; Ghosh, S.; Gray, R.S.; Lewis, R.A.; Johnson, C.A.; Attie-Bittach, T.; Katsanis, N.; Wallingford, J.B. Planar cell polarity acts through septins to control collective cell movement and ciliogenesis. Science, 2010, 329, 1337-1340.
117. Huang, P.; Schier, A.F. Dampened Hedgehog signaling but normal Wnt signaling in zebrafish without cilia. Development, 2009, 136, 3089-3098.
118. Ocbina, P.J.; Tuson, M.; Anderson, K.V. Primary cilia are not required for normal canonical Wnt signaling in the mouse embryo. PLoS One, 2009, 4, e6839.
119. Wallingford, J.B.; Mitchell, B. Strange as it may seem: the many links between Wnt signaling, planar cell polarity, and cilia. Genes Dev., 2011, 25, 201-213.
120. Bukanov, N.O.; Smith, L.A.; Klinger, K.W.; Ledbetter, S.R.; Ibraghimov-Beskrovnaya, O. Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature, 2006, 444, 949-952.
121. Seeley, E.S.; Carrière, C.; Goetze, T.; Longnecker, D.S.; Korc, M. Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia. Cancer Res., 2009, 69, 422-430.
122. Schraml, P.; Frew, I.J.; Thoma, C.R.; Boysen, G.; Struckmann, K.; Krek, W.; Moch, H. Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia. Mod. Pathol., 2009, 22, 31-36.
123. Chizhikov, V.V.; Davenport, J.; Zhang, Q.; Shih, E.K.; Cabello, O.A.; Fuchs, J.L.; Yoder, B.K.; Millen, K.J. Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. J. Neurosci., 2007, 27, 9780-9789.
124. Spassky, N.; Han, Y.G.; Aguilar, A.; Strehl, L.; Besse, L.; Laclef, C.; Ros, M.R.; Garcia-Verdugo, J.M.; Alvarez-Buylla, A. Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool. Dev. Biol., 2008, 317, 246-259.
125. Han, Y.G.; Kim, H.J.; Dlugosz, A.A.; Ellison, D.W.; Gilbertson, R.J.; Alvarez-Buylla, A. Dual and opposing roles of primary cilia in medulloblastoma development. Nat. Med., 2009, 15, 1062-1065.
126. Han, Y.G.; Alvarez-Buylla, A. Role of primary cilia in brain development and cancer. Curr. Opin. Neurobiol., 2010, 20, 58-67.
127. Gherman, A.; Davis, E.E.; Katsanis, N. The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat. Genet., 2006, 38, 961-962.
128. Boehlke, C.; Kotsis, F.; Patel, V.; Braeg, S.; Voelker, H.; Bredt, S.; Beyer, T.; Janusch, H.; Hamann, C.; Gödel, M.; Müller, K.; Herbst, M.; Hornung, M.; Doerken, M.; Köttgen, M.; Nitschke, R.; Igarashi, P.; Walz, G.; Kuehn, E.W. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat. Cell Biol., 2010, 12, 1115-1122.