Mechanisms and functions of Hedgehog signalling across the metazoa

Nature Reviews Genetics

Volumn 12, Issue 6, 2011, Pages 393-406

  Ingham, Philip W ^a,b   Nakano, Yoshiro ^a,c   Seger, Claudia ^a  

^a INSTITUTE OF MOLECULAR AND CELL BIOLOGY   (Singapore)

^b NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^c HYOGO COLLEGE OF MEDICINE   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR;

ANNELID WORM; ARTHROPOD; CLINICAL PATHWAY; DOWNSTREAM PROCESSING; DROSOPHILA MELANOGASTER; GENE SEQUENCE; GENETIC ANALYSIS; HOMEOSTASIS; METAZOON; NONHUMAN; PHYLOGENY; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; SIGNAL TRANSDUCTION; TURBELLARIA;

ANIMALS; CILIA; DROSOPHILA MELANOGASTER; GENE EXPRESSION REGULATION; GENOME; HEDGEHOG PROTEINS; HUMANS; LIGANDS; LIPIDS; MICE; MODELS, GENETIC; PHYLOGENY; PROTEIN STRUCTURE, TERTIARY; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS;

ERINACEIDAE; METAZOA; MUS;

EID: 79956308325     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg2984     Document Type: Review

References (157)

1. Ingham, P. W. Transducing Hedgehog: the story so far. EMBO J. 17, 3505-3511 (1998). (Pubitemid 28327369)
2. Hao, L., Johnsen, R., Lauter, G., Baillie, D. & Burglin, T. R. Comprehensive analysis of gene expression patterns of hedgehog-related genes. BMC Genomics 7, 280 (2006).
3. Beachy, P. A. et al. Multiple roles of cholesterol in hedgehog protein biogenesis and signaling. Cold Spring Harb. Symp. Quant. Biol. 62, 191-204 (1997). (Pubitemid 28198537)
4. Ingham, P. W., Taylor, A. M. & Nakano, Y. Role of the Drosophila patched gene in positional signalling. Nature 353, 184-187 (1991). (Pubitemid 21912487)
5. Marigo, V., Davey, R. A., Zuo, Y., Cunningham, J. M. & Tabin, C. J. Biochemical evidence that Patched is the Hedgehog receptor. Nature 384, 176-179 (1996). (Pubitemid 26386474)
6. Zheng, X., Mann, R. K., Sever, N. & Beachy, P. A. Genetic and biochemical definition of the Hedgehog receptor. Genes Dev. 24, 57-71 (2011).
7. Ayers, K. L. & Therond, P. P. Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling. Trends Cell Biol. 20, 287-298 (2010).
8. Lee, J. J. et al. Autoproteolysis in hedgehog protein biogenesis. Science 266, 1528-1537 (1994).
9. Bürglin, T. R. The Hedgehog protein family. Genome Biol. 9, 241 (2008).
10. Koonin, E. V. A protein splice-junction motif in hedgehog family proteins. Trends Biochem. Sci. 20, 141-142 (1995).
11. Bürglin, T. R. Evolution of hedgehog and hedgehog-related genes, their origin from Hog proteins in ancestral eukaryotes and discovery of a novel Hint motif. BMC Genomics 9, 127 (2008).
12. Snell, E. A. et al. An unusual choanoflagellate protein released by Hedgehog autocatalytic processing. Proc. Biol. Sci. 273, 401-407 (2006). (Pubitemid 46780546)
13. Fuse, N. et al. Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for patched. Proc. Natl Acad. Sci. USA 96, 10992-10999 (1999). (Pubitemid 29487317)
14. King, N. et al. The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans. Nature 451, 783-788 (2008). (Pubitemid 351253174)
15. Adamska, M. et al. The evolutionary origin of hedgehog proteins. Curr. Biol. 17, R836-R837 (2007). (Pubitemid 47503799)
16. Matus, D. Q., Magie, C. R., Pang, K., Martindale, M. Q. & Thomsen, G. H. The Hedgehog gene family of the cnidarian, Nematostella vectensis, and implications for understanding metazoan Hedgehog pathway evolution. Dev. Biol. 313, 501-518 (2008).
17. Avaron, F., Hoffman, L., Guay, D. & Akimenko, M. A. Characterization of two new zebrafish members of the hedgehog family: atypical expression of a zebrafish indian hedgehog gene in skeletal elements of both endochondral and dermal origins. Dev. Dyn. 235, 478-489 (2006). (Pubitemid 43100953)
18. Chamoun, Z. et al. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293, 2080-2084 (2001). (Pubitemid 32848055)
19. Chen, M. H., Li, Y. J., Kawakami, T., Xu, S. M. & Chuang, P. T. Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev. 18, 641-659 (2004). (Pubitemid 38489933)
20. Peters, C., Wolf, A., Wagner, M., Kuhlmann, J. & Waldmann, H. The cholesterol membrane anchor of the Hedgehog protein confers stable membrane association to lipid-modified proteins. Proc. Natl Acad. Sci. USA 101, 8531-8536 (2004). (Pubitemid 38745804)
21. Burke, R. et al. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 99, 803-815 (1999). (Pubitemid 30017650)
22. Caspary, T. et al. Mouse Dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr. Biol. 12, 1628-1632 (2002).
23. Kawakami, T. et al. Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development 129, 5753-5765 (2002). (Pubitemid 36054618)
24. Ma, Y. et al. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111, 63-75 (2002).
25. Lewis, P. M. et al. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 105, 599-612 (2001). (Pubitemid 32524113)
26. Gallet, A., Ruel, L., Staccini-Lavenant, L. & Therond, P. P. Cholesterol modification is necessary for controlled planar long-range activity of Hedgehog in Drosophila epithelia. Development 133, 407-418 (2006). (Pubitemid 43273827)
27. Zeng, X. et al. A freely diffusible form of Sonic hedgehog mediates long-range signalling. Nature 411, 716-720 (2001). (Pubitemid 32531680)
28. Eugster, C., Panakova, D., Mahmoud, A. & Eaton, S. Lipoprotein-heparan sulfate interactions in the Hh pathway. Dev. Cell 13, 57-71 (2007). (Pubitemid 46972032)
29. Panakova, D., Sprong, H., Marois, E., Thiele, C. & Eaton, S. Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature 435, 58-65 (2005). (Pubitemid 40655904)
30. Lum, L. et al. Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol. Cell 12, 1261-1274 (2003). (Pubitemid 37487933)
31. Vyas, N. et al. Nanoscale organization of hedgehog is essential for long-range signaling. Cell 133, 1214-1227 (2008). (Pubitemid 351852915)
32. Ayers, K. L., Gallet, A., Staccini-Lavenant, L. & Therond, P. P. The long-range activity of Hedgehog is regulated in the apical extracellular space by the glypican Dally and the hydrolase Notum. Dev. Cell 18, 605-620 (2010).
33. Williams, E. H. et al. Dally-like core protein and its mammalian homologues mediate stimulatory and inhibitory effects on Hedgehog signal response. Proc. Natl Acad. Sci. USA 107, 5869-5874 (2010).
34. Su, V. F., Jones, K. A., Brodsky, M. & The, I. Quantitative analysis of Hedgehog gradient formation using an inducible expression system. BMC Dev. Biol. 7, 43 (2007).
35. Callejo, A., Torroja, C., Quijada, L. & Guerrero, I. Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix. Development 133, 471-483 (2006). (Pubitemid 43273833)
36. Chamberlain, C. E., Jeong, J., Guo, C., Allen, B. L. & McMahon, A. P. Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning. Development 135, 1097-1106 (2008). (Pubitemid 351578138)
37. Hartman, T. R. et al. Drosophila Boi limits Hedgehog levels to suppress follicle stem cell proliferation. J. Cell Biol. 191, 943-952 (2010).
38. Richards, G. S. & Degnan, B. M. The dawn of developmental signaling in the metazoa. Cold Spring Harb. Symp. Quant. Biol. 74, 81-90 (2009).
39. Bishop, B. et al. Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. Nature Struct. Mol. Biol. 16, 698-703 (2009).
40. Yam, P. T., Langlois, S. D., Morin, S. & Charron, F. Sonic hedgehog guides axons through a noncanonical, Src-family-kinase-dependent signaling pathway. Neuron 62, 349-362 (2009).
41. Dai, P. et al. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J. Biol. Chem. 274, 8143-8152 (1999).
42. Gustafsson, M. K. et al. Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification. Genes Dev. 16, 114-126 (2002). (Pubitemid 34049642)
43. Sasaki, H., Hui, C., Nakafuku, M. & Kondoh, H. A binding site for Gli proteins is essential for HNF?3β floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 124, 1313-1322 (1997). (Pubitemid 27190104)
44. Alexandre, C., Jacinto, A. & Ingham, P. W. Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the cubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins. Genes Dev. 10, 2003-2013 (1996). (Pubitemid 26346109)
45. Vokes, S. A., Ji, H., Wong, W. H. & McMahon, A. P. A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev. 22, 2651-2663 (2008).
46. Vokes, S. A. et al. Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development 134, 1977-1989 (2007). (Pubitemid 46939242)
47. Hallikas, O. et al. Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell 124, 47-59 (2006). (Pubitemid 43069309)
48. Goodrich, L. V., Johnson, R. L., Milenkovic, L., McMahon, J. A. & Scott, M. P. Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev. 10, 301-312 (1996). (Pubitemid 26058963)
49. Duman-Scheel, M., Weng, L., Xin, S. & Du, W. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature 417, 299-304 (2002). (Pubitemid 34534713)
50. Kenney, A. M. & Rowitch, D. H. Sonic hedgehog promotes G1 cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol. Cell. Biol. 20, 9055-9067 (2000). (Pubitemid 32245934)
51. Sasaki, H., Nishizaki, Y., Hui, C., Nakafuku, M. & Kondoh, H. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 126, 3915-3924 (1999). (Pubitemid 29440488)
52. Srivastava, M. et al. The Amphimedon queenslandica genome and the evolution of animal complexity. Nature 466, 720-726 (2010).
53. Aza-Blanc, P., Ramirez-Weber, F. A., Laget, M. P., Schwartz, C. & Kornberg, T. B. Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 89, 1043-1053 (1997). (Pubitemid 127678738)
54. Bai, C. B., Stephen, D. & Joyner, A. L. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev. Cell 6, 103-115 (2004). (Pubitemid 38089209)
55. Varga, Z. M. et al. Zebrafish smoothened functions in ventral neural tube specification and axon tract formation. Development 128, 3497-3509 (2001). (Pubitemid 32962718)
56. Alcedo, J., Ayzenzon, M., Von Ohlen, T., Noll, M. & Hooper, J. E. The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell 86, 221-232 (1996). (Pubitemid 26286105)
57. Van Den Heuvel, M. & Ingham, P. W. smoothened encodes a receptor-like serpentine protein required for hedgehog signalling. Nature 382, 547-551 (1996). (Pubitemid 26260698)
58. Chen, W., Burgess, S. & Hopkins, N. Analysis of the zebrafish smoothened mutant reveals conserved and divergent functions of hedgehog activity. Development 128, 2385-2396 (2001). (Pubitemid 32633370)
59. Zhang, X. M., Ramalho-Santos, M. & McMahon, A. P. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 106, 781-792 (2001). (Pubitemid 32635107)
60. Beachy, P. A., Hymowitz, S. G., Lazarus, R. A., Leahy, D. J. & Siebold, C. Interactions between Hedgehog proteins and their binding partners come into view. Genes Dev. 24, 2001-2012 (2010).
61. Tenzen, T. et al. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev. Cell 10, 647-656 (2006).
62. Srivastava, M. et al. The Trichoplax genome and the nature of placozoans. Nature 454, 955-960 (2008).
63. McLellan, J. S. et al. The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. Nature 455, 979-983 (2008).
64. Murone, M., Rosenthal, A. & De Sauvage, F. J. Sonic hedgehog signaling by the patched-smoothened receptor complex. Curr. Biol. 9, 76-84 (1999). (Pubitemid 29083531)
65. Taipale, J., Cooper, M. K., Maiti, T. & Beachy, P. A. Patched acts catalytically to suppress the activity of Smoothened. Nature 418, 892-897 (2002). (Pubitemid 34966310)
66. Tseng, T. T. et al. The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J. Mol. Microbiol. Biotechnol. 1, 107-125 (1999).
67. Chen, J. K., Taipale, J., Cooper, M. K. & Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16, 2743-2748 (2002). (Pubitemid 35253140)
68. Yavari, A. et al. Role of lipid metabolism in smoothened derepression in hedgehog signaling. Dev. Cell 19, 54-65 (2010).
69. Price, M. A. & Kalderon, D. Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell 108, 823-835 (2002). (Pubitemid 34327533)
70. Wang, B., Fallon, J. F. & Beachy, P. A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423-434 (2000).
71. Pan, Y., Wang, C. & Wang, B. Phosphorylation of Gli2 by protein kinase A is required for Gli2 processing and degradation and the Sonic Hedgehog-regulated mouse development. Dev. Biol. 326, 177-189 (2009).
72. Jia, J. et al. Phosphorylation by double-time/CKIepsilon and CKIα targets cubitus interruptus for Slimb/β-TRCP-mediated proteolytic processing. Dev. Cell 9, 819-830 (2005). (Pubitemid 41724109)
73. Tempe, D., Casas, M., Karaz, S., Blanchet-Tournier, M. F. & Concordet, J. P. Multisite protein kinase A and glycogen synthase kinase 3β phosphorylation leads to Gli3 ubiquitination by SCFβTrCP. Mol. Cell. Biol. 26, 4316-4326 (2006). (Pubitemid 43788030)
74. Forbes, A. J., Nakano, Y., Taylor, A. M. & Ingham, P. W. Genetic analysis of hedgehog signalling in the Drosophila embryo. Dev. Suppl. 115-124 (1993). (Pubitemid 24139753)
75. Robbins, D. J. et al. Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Cell 90, 225-234 (1997). (Pubitemid 27329708)
76. Sisson, J. C., Ho, K. S., Suyama, K. & Scott, M. P. Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell 90, 235-245 (1997). (Pubitemid 27329709)
77. Kollmar, M. & Glockner, G. Identification and phylogenetic analysis of Dictyostelium discoideum kinesin proteins. BMC Genomics 4, 47 (2003).
78. Farzan, S. F. et al. Costal2 functions as a kinesin-like protein in the hedgehog signal transduction pathway. Curr. Biol. 18, 1215-1220 (2008).
79. Liu, Y., Cao, X., Jiang, J. & Jia, J. Fused-Costal2 protein complex regulates Hedgehog-induced Smo phosphorylation and cell-surface accumulation. Genes Dev. 21, 1949-1963 (2007). (Pubitemid 47204933)
80. Stegman, M. A. et al. Identification of a tetrameric hedgehog signaling complex. J. Biol. Chem. 275, 21809-21812 (2000). (Pubitemid 30621748)
81. Zhang, W. et al. Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Dev. Cell 8, 267-278 (2005). (Pubitemid 40197742)
82. Oh, S. A. et al. A divergent cellular role for the FUSED kinase family in the plant-specific cytokinetic phragmoplast. Curr. Biol. 15, 2107-2111 (2005). (Pubitemid 41739742)
83. Tang, L. et al. tsunami, the Dictyostelium homolog of the Fused kinase, is required for polarization and chemotaxis. Genes Dev. 22, 2278-2290 (2008).
84. Ruel, L. et al. Phosphorylation of the atypical kinesin Costal2 by the kinase Fused induces the partial disassembly of the Smoothened-Fused-Costal2- Cubitus interruptus complex in Hedgehog signalling. Development 134, 3677-3689 (2007). (Pubitemid 350104377)
85. Das, D. et al. The crystal structure of a bacterial Sufu-like protein defines a novel group of bacterial proteins that are similar to the N-terminal domain of human Sufu. Protein Sci. 19, 2131-2140 (2010).
86. Ruel, L., Rodriguez, R., Gallet, A., Lavenant-Staccini, L. & Therond, P. P. Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nature Cell Biol. 5, 907-913 (2003). (Pubitemid 37220697)
87. Apionishev, S., Katanayeva, N. M., Marks, S. A., Kalderon, D. & Tomlinson, A. Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nature Cell Biol. 7, 86-92 (2005). (Pubitemid 40123387)
88. Wang, G., Amanai, K., Wang, B. & Jiang, J. Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus. Genes Dev. 14, 2893-2905 (2000).
89. Methot, N. & Basler, K. Suppressor of fused opposes hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development 127, 4001-4010 (2000).
90. Svard, J. et al. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev. Cell 10, 187-197 (2006). (Pubitemid 43174952)
91. Cooper, A. F. et al. Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development 132, 4407-4417 (2005). (Pubitemid 41576701)
92. Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109-1113 (1997). (Pubitemid 27371635)
93. Humke, E. W., Dorn, K. V., Milenkovic, L., Scott, M. P. & Rohatgi, R. The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins. Genes Dev. 24, 670-682 (2010).
94. Kise, Y., Morinaka, A., Teglund, S. & Miki, H. Sufu recruits GSK3β for efficient processing of Gli3. Biochem. Biophys. Res. Commun. 387, 569-574 (2009).
95. Rink, J. C., Gurley, K. A., Elliott, S. A. & Sanchez Alvarado, A. Planarian Hh signaling regulates regeneration polarity and links Hh pathway evolution to cilia. Science 326, 1406-1410 (2009).
96. Yazawa, S., Umesono, Y., Hayashi, T., Tarui, H. & Agata, K. Planarian Hedgehog/Patched establishes anterior-posterior polarity by regulating Wnt signaling. Proc. Natl Acad. Sci. USA 106, 22329-22334 (2009).
97. Goetz, S. C. & Anderson, K. V. The primary cilium: a signalling centre during vertebrate development. Nature Rev. Genet. 11, 331-344 (2010).
98. Han, Y. G., Kwok, B. H. & Kernan, M. J. Intraflagellar transport is required in Drosophila to differentiate sensory cilia but not sperm. Curr. Biol. 13, 1679-1686 (2003). (Pubitemid 37216245)
99. Rohatgi, R., Milenkovic, L. & Scott, M. P. Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372-376 (2007). (Pubitemid 47106377)
100. Haycraft, C. J. et al. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 1, e53 (2005).
101. Endoh-Yamagami, S. et al. The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr. Biol. 19, 1320-1326 (2009).
102. Tukachinsky, H., Lopez, L. V. & Salic, A. A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J. Cell Biol. 191, 415-428 (2010).
103. Merchant, M. et al. Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol. Cell. Biol. 25, 7054-7068 (2005). (Pubitemid 41105904)
104. Wilson, C. W. et al. Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis. Nature 459, 98-102 (2009).
105. Evangelista, M. et al. Kinome siRNA screen identifies regulators of ciliogenesis and hedgehog signal transduction. Sci. Signal. 1, ra7 (2008).
106. Cheung, H. O. et al. The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci. Signal. 2, ra29 (2009).
107. Liem, K. F., Jr, He, M., Ocbina, P. J. & Anderson, K. V. Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc. Natl Acad. Sci. USA 106, 13377-13382 (2009).
108. Doxsey, S., Zimmerman, W. & Mikule, K. Centrosome control of the cell cycle. Trends Cell Biol. 15, 303-311 (2005). (Pubitemid 40805326)
109. Wigley, W. C. et al. Dynamic association of proteasomal machinery with the centrosome. J. Cell Biol. 145, 481-490 (1999).
110. Barzi, M., Berenguer, J., Menendez, A., Alvarez-Rodriguez, R. & Pons, S. Sonic-hedgehog- mediated proliferation requires the localization of PKA to the cilium base. J. Cell Sci. 123, 62-69 (2010).
111. Kim, H. R., Richardson, J., van Eeden, F. & Ingham, P. W. Gli2a protein localization reveals a role for Iguana/DZIP1 in primary ciliogenesis and a dependence of Hedgehog signal transduction on primary cilia in the zebrafish. BMC Biol. 8, 65 (2010).
112. Tay, S. Y. et al. The iguana/DZIP1 protein is a novel component of the ciliogenic pathway essential for axonemal biogenesis. Dev. Dyn. 239, 527-534 (2010).
113. Glazer, A. M. et al. The Zn finger protein Iguana impacts Hedgehog signaling by promoting ciliogenesis. Dev. Biol. 337, 148-156 (2010).
114. Ingham, P. W. & Placzek, M. Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nature Rev. Genet. 7, 841-850 (2006). (Pubitemid 44607100)
115. McMahon, A. P., Ingham, P. W. & Tabin, C. J. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 53, 1-114 (2003). (Pubitemid 137639458)
116. Taipale, J. & Beachy, P. A. The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349-354 (2001). (Pubitemid 32467044)
117. Ingham, P. W. & Hidalgo, A. Regulation of wingless transcription in the Drosophila embryo. Development 117, 283-291 (1993). (Pubitemid 23094175)
118. Ingham, P. W. Localized hedgehog activity controls spatial limits of wingless transcription in the Drosophila embryo. Nature 366, 560-562 (1993). (Pubitemid 24035994)
119. Alexandre, C., Lecourtois, M. & Vincent, J. Wingless and Hedgehog pattern Drosophila denticle belts by regulating the production of short-range signals. Development 126, 5689-5698 (1999). (Pubitemid 30035017)
120. Farzana, L. & Brown, S. J. Hedgehog signaling pathway function conserved in Tribolium segmentation. Dev. Genes Evol. 218, 181-192 (2008). (Pubitemid 351513917)
121. Simonnet, F., Deutsch, J. & Queinnec, E. hedgehog is a segment polarity gene in a crustacean and a chelicerate. Dev. Genes Evol. 214, 537-545 (2004). (Pubitemid 39490189)
122. Dray, N. et al. Hedgehog signaling regulates segment formation in the annelid Platynereis. Science 329, 339-342 (2010).
123. Kang, D. et al. A hedgehog homolog regulates gut formation in leech (Helobdella). Development 130, 1645-1657 (2003). (Pubitemid 36527523)
124. Seaver, E. C. & Kaneshige, L. M. Expression of 'segmentation' genes during larval and juvenile development in the polychaetes Capitella sp. I and H. elegans. Dev. Biol. 289, 179-194 (2006). (Pubitemid 41804097)
125. Petersen, C. P. & Reddien, P. W. Smed-βcatenin-1 is required for anteroposterior blastema polarity in planarian regeneration. Science 319, 327-330 (2008).
126. Petersen, C. P. & Reddien, P. W. A wound-induced Wnt expression program controls planarian regeneration polarity. Proc. Natl Acad. Sci. USA 106, 17061-17066 (2009).
127. Yamaguchi, T. P. Heads or tails: Wnts and anterior-posterior patterning. Curr. Biol. 11, R713-R724 (2001). (Pubitemid 32835869)
128. Dessaud, E., McMahon, A. P. & Briscoe, J. Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network. Development 135, 2489-2503 (2008).
129. Ramalho-Santos, M., Melton, D. A. & McMahon, A. P. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127, 2763-2772 (2000). (Pubitemid 30426822)
130. Walton, K. D., Croce, J. C., Glenn, T. D., Wu, S. Y. & McClay, D. R. Genomics and expression profiles of the Hedgehog and Notch signaling pathways in sea urchin development. Dev. Biol. 300, 153-164 (2006). (Pubitemid 44834387)
131. Walton, K. D., Warner, J., Hertzler, P. H. & McClay, D. R. Hedgehog signaling patterns mesoderm in the sea urchin. Dev. Biol. 331, 26-37 (2009).
132. Mao, J., Kim, B. M., Rajurkar, M., Shivdasani, R. A. & McMahon, A. P. Hedgehog signaling controls mesenchymal growth in the developing mammalian digestive tract. Development 137, 1721-1729 (2010).
133. Madison, B. B. et al. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development 132, 279-289 (2005). (Pubitemid 40268278)
134. Crosnier, C., Stamataki, D. & Lewis, J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nature Rev. Genet. 7, 349-359 (2006).
135. Takashima, S., Mkrtchyan, M., Younossi-Hartenstein, A., Merriam, J. R. & Hartenstein, V. The behaviour of Drosophila adult hindgut stem cells is controlled by Wnt and Hh signalling. Nature 454, 651-655 (2008).
136. Shin, K. et al. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells bladder. Nature 427, 110-114 (2011).
137. Retaux, S., Pottin, K. & Alunni, A. Shh and forebrain evolution in the blind cavefish Astyanax mexicanus. Biol. Cell 100, 139-147 (2008). (Pubitemid 351372673)
138. Retaux, S. & Kano, S. Midline signaling and evolution of the forebrain in chordates: a focus on the lamprey hedgehog case. Integrative Comparitive Biol. 50, 98-109 (2010).
139. Kano, S. et al. Two lamprey Hedgehog genes share non-coding regulatory sequences and expression patterns with gnathostome Hedgehogs. PLoS ONE 5, e13332.
140. Keys, D. N. et al. Recruitment of a hedgehog regulatory circuit in butterfly eyespot evolution. Science 283, 532-534 (1999).
141. Mas, C. & Ruiz i Altaba, A. Small molecule modulation of HH-GLI signaling: current leads, trials and tribulations. Biochem. Pharmacol. 80, 712-723 (2010).
142. Low, J. A. & De Sauvage, F. J. Clinical experience with Hedgehog pathway inhibitors. J. Clin. Oncol. 28, 5321-5326 (2010).
143. Nakano, Y. et al. Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila. Mech. Dev. 121, 507-518 (2004). (Pubitemid 38681206)
144. Aanstad, P. et al. The extracellular domain of Smoothened regulates ciliary localization and is required for high-level Hh signaling. Curr. Biol. 19, 1034-1039 (2009).
145. Ogden, S. K. et al. G protein Gαi functions immediately downstream of Smoothened in Hedgehog signalling. Nature 456, 967-970 (2008).
146. Malpel, S. et al. The last 59 amino acids of Smoothened cytoplasmic tail directly bind the protein kinase Fused and negatively regulate the Hedgehog pathway. Dev. Biol. 303, 121-133 (2007). (Pubitemid 46241093)
147. Wolff, C., Roy, S. & Ingham, P. W. Multiple muscle cell identities induced by distinct levels and timing of hedgehog activity in the zebrafish embryo. Curr. Biol. 13, 1169-1181 (2003). (Pubitemid 36872939)
148. Zhao, Y., Tong, C. & Jiang, J. Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450, 252-258 (2007). (Pubitemid 350100532)
149. Chen, Y. et al. G protein-coupled receptor kinase 2 promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in Drosophila. Genes Dev. 24, 2054-2067 (2010).
150. Philipp, M. et al. Smoothened signaling in vertebrates is facilitated by a G protein-coupled receptor kinase. Mol. Biol. Cell 19, 5478-5489 (2008).
151. Corbit, K. C. et al. Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018-1021 (2005). (Pubitemid 41486982)
152. Kuwabara, P. E. & Labouesse, M. The sterol-sensing domain: multiple families, a unique role? Trends Genet. 18, 193-201 (2002). (Pubitemid 34273740)
153. Hausmann, G., von Mering, C. & Basler, K. The hedgehog signaling pathway: where did it come from? PLoS Biol. 7, e1000146 (2009).
154. Halbleib, J. M. & Nelson, W. J. Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev. 20, 3199-3214 (2006). (Pubitemid 44904842)
155. Chen, X. et al. Processing and turnover of the Hedgehog protein in the endoplasmic reticulum. J. Cell Biol. 192, 825-838 (2011).
156. Abel, E. S. et al. Possible roles of protein kinase A in cell motility and excystation of the early diverging eukaryote Giardia lamblia. J. Biol. Chem. 276, 10320-10329 (2001).
157. Pitsouli, C. & Perrimon, N. Developmental biology: our fly cousins' gut. Nature 454, 592-593 (2008).