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  • Review Article
  • Published:

Mechanisms and functions of Hedgehog signalling across the metazoa

Key Points

  • Hedgehog proteins are members of one of a small number of signalling factor families that are crucial for progenitor cell specification and stem cell maintenance in animal development.

  • Dysfunction of Hedgehog signalling can promote a variety of tumours, making the pathway an important drug target.

  • The range and potency of Hedgehog proteins depends on their unusual dual lipid modification.

  • Hedgehog signalling arose early in the evolution of multicellular organisms through the redeployment of components found in unicellular organisms.

  • Hedgehog proteins bind to and inactivate a transporter-like protein, Patched, which regulates a G protein-coupled receptor-like protein, Smoothened.

  • Smoothened regulates an intracellular signalling complex that includes a kinesin family member, KIF7, and the GLI zinc finger transcription factors.

  • The primary cilium is crucial for the processing of Hedeghog signalling throughout the vertebrates.

  • Hedgehog signalling has important roles in anteroposterior polarity in invertebrates and in gut development throughout the animal kingdom.

Abstract

Hedgehog proteins constitute one of a small number of families of secreted signals that have a central role in the development of metazoans. Genetic analyses in flies, fish and mice have uncovered the major components of the pathway that transduces Hedgehog signals, and recent genome sequence projects have provided clues about its evolutionary origins. In this Review we provide an updated overview of the mechanisms and functions of this signalling pathway, highlighting the conserved and divergent features of the pathway, as well as some of the common themes in its deployment that have emerged from recent studies.

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Figure 1: Structure of Hedgehog and Hedgehog-related proteins.
Figure 2: Lipid modification and release of the Hedgehog ligand.
Figure 3: Conservation of individual molecules across species with phylogenetic representation.
Figure 4: The Hedgehog signalling pathway in Drosophila melanogaster.
Figure 5: Conserved roles of Hedgehog signalling between phyla.

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References

  1. Ingham, P. W. Transducing Hedgehog: the story so far. EMBO J. 17, 3505–3511 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  4. Ingham, P. W., Taylor, A. M. & Nakano, Y. Role of the Drosophila patched gene in positional signalling. Nature 353, 184–187 (1991).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  8. Lee, J. J. et al. Autoproteolysis in hedgehog protein biogenesis. Science 266, 1528–1537 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Bürglin, T. R. The Hedgehog protein family. Genome Biol. 9, 241 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Koonin, E. V. A protein splice-junction motif in hedgehog family proteins. Trends Biochem. Sci. 20, 141–142 (1995).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Snell, E. A. et al. An unusual choanoflagellate protein released by Hedgehog autocatalytic processing. Proc. Biol. Sci. 273, 401–407 (2006).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. King, N. et al. The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans. Nature 451, 783–788 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Adamska, M. et al. The evolutionary origin of hedgehog proteins. Curr. Biol. 17, R836–R837 (2007).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  18. Chamoun, Z. et al. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293, 2080–2084 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  22. Caspary, T. et al. Mouse Dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr. Biol. 12, 1628–1632 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Kawakami, T. et al. Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development 129, 5753–5765 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Ma, Y. et al. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111, 63–75 (2002).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  27. Zeng, X. et al. A freely diffusible form of Sonic hedgehog mediates long-range signalling. Nature 411, 716–720 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Eugster, C., Panakova, D., Mahmoud, A. & Eaton, S. Lipoprotein-heparan sulfate interactions in the Hh pathway. Dev. Cell 13, 57–71 (2007).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  31. Vyas, N. et al. Nanoscale organization of hedgehog is essential for long-range signaling. Cell 133, 1214–1227 (2008).

    Article  CAS  PubMed  Google Scholar 

  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). Elegant genetic analysis implicating apically secreted HH in long-range signalling in the D. melanogaster imaginal disc and the roles of Dally and notum in promoting its release.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  37. Hartman, T. R. et al. Drosophila Boi limits Hedgehog levels to suppress follicle stem cell proliferation. J. Cell Biol. 191, 943–952 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  41. Dai, P. et al. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J. Biol. Chem. 274, 8143–8152 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sasaki, H., Hui, C., Nakafuku, M. & Kondoh, H. A binding site for Gli proteins is essential for HNF-3 β floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 124, 1313–1322 (1997).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). The first genome-scale identification of HH and GLI target genes using chromatin immunoprecipitation– chip analysis in the mouse limb.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vokes, S. A. et al. Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development 134, 1977–1989 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Hallikas, O. et al. Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell 124, 47–59 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  52. Srivastava, M. et al. The Amphimedon queenslandica genome and the evolution of animal complexity. Nature 466, 720–726 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  55. Varga, Z. M. et al. Zebrafish smoothened functions in ventral neural tube specification and axon tract formation. Development 128, 3497–3509 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  57. van den Heuvel, M. & Ingham, P. W. smoothened encodes a receptor-like serpentine protein required for hedgehog signalling. Nature 382, 547–551 (1996).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  62. Srivastava, M. et al. The Trichoplax genome and the nature of placozoans. Nature 454, 955–960 (2008).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Murone, M., Rosenthal, A. & de Sauvage, F. J. Sonic hedgehog signaling by the patched-smoothened receptor complex. Curr. Biol. 9, 76–84 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yavari, A. et al. Role of lipid metabolism in smoothened derepression in hedgehog signaling. Dev. Cell 19, 54–65 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  77. Kollmar, M. & Glockner, G. Identification and phylogenetic analysis of Dictyostelium discoideum kinesin proteins. BMC Genomics 4, 47 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Stegman, M. A. et al. Identification of a tetrameric hedgehog signaling complex. J. Biol. Chem. 275, 21809–21812 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Zhang, W. et al. Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Dev. Cell 8, 267–278 (2005).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). This paper, together with reference 90, describes the generation of targeted mutant alleles of the mouse Sufu gene and the surprising finding that SUFU has an essential role in negatively regulating the HH pathway in mammals.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). Careful study of the role of SUFU based on analysis of the endogenous GLI proteins in tissue culture cells, establishing the central role of SUFU in regulating GLI processing, stability and activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). This paper and reference 95 describe the identification of HH pathway components in planarians and the first functional analysis of their role in regeneration. Reference 95 also presents evidence that HH signalling is independent of cilia in planarians.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Goetz, S. C. & Anderson, K. V. The primary cilium: a signalling centre during vertebrate development. Nature Rev. Genet. 11, 331–344 (2010).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  99. Rohatgi, R., Milenkovic, L. & Scott, M. P. Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372–376 (2007). An elegant study describing the generation of high-quality antibodies recognizing the mammalian SMO and PTC1 proteins and their use in studying the mutually exclusive patterns of ciliary localization of PTC1 and SMO in response to SHH activity.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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). Generation of a targeted mutation in the mouse COS2 orthologue, KIF7, demonstrating the previously disputed functional conservation of the protein in HH signalling from D. melanogaster to mouse and its role in regulating GLI3 trafficking in the primary cilium.

    Article  CAS  PubMed  Google Scholar 

  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). Careful analysis of the dynamics of SUFU and GLI localization and the role of SMO in promoting their dissociation in the primary cilium in response to SHH.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wilson, C. W. et al. Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis. Nature 459, 98–102 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Evangelista, M. et al. Kinome siRNA screen identifies regulators of ciliogenesis and hedgehog signal transduction. Sci. Signal. 1, ra7 (2008).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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). Isolation of a chemically induced missense mutation in the mouse COS2 orthologue, KIF7, demonstrating the previously disputed functional conservation of the protein in HH signalling from D. melanogaster to mouse and the role of its motor domain in trafficking in the primary cilium.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Doxsey, S., Zimmerman, W. & Mikule, K. Centrosome control of the cell cycle. Trends Cell Biol. 15, 303–311 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Wigley, W. C. et al. Dynamic association of proteasomal machinery with the centrosome. J. Cell Biol. 145, 481–490 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  113. Glazer, A. M. et al. The Zn finger protein Iguana impacts Hedgehog signaling by promoting ciliogenesis. Dev. Biol. 337, 148–156 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Ingham, P. W. & Placzek, M. Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nature Rev. Genet. 7, 841–850 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  116. Taipale, J. & Beachy, P. A. The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354 (2001).

    Article  CAS  PubMed  Google Scholar 

  117. Ingham, P. W. & Hidalgo, A. Regulation of wingless transcription in the Drosophila embryo. Development 117, 283–291 (1993).

    Article  CAS  PubMed  Google Scholar 

  118. Ingham, P. W. Localized hedgehog activity controls spatial limits of wingless transcription in the Drosophila embryo. Nature 366, 560–562 (1993).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  120. Farzana, L. & Brown, S. J. Hedgehog signaling pathway function conserved in Tribolium segmentation. Dev. Genes Evol. 218, 181–192 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  122. Dray, N. et al. Hedgehog signaling regulates segment formation in the annelid Platynereis. Science 329, 339–342 (2010). Functional analysis of HH signalling in this annelid species providing the first evidence that the role of HH signalling in segmentation is conserved across phyla.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kang, D. et al. A hedgehog homolog regulates gut formation in leech (Helobdella). Development 130, 1645–1657 (2003).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  125. Petersen, C. P. & Reddien, P. W. Smed-βcatenin-1 is required for anteroposterior blastema polarity in planarian regeneration. Science 319, 327–330 (2008).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Yamaguchi, T. P. Heads or tails: Wnts and anterior-posterior patterning. Curr. Biol. 11, R713–R724 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  129. Ramalho-Santos, M., Melton, D. A. & McMahon, A. P. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127, 2763–2772 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Madison, B. B. et al. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development 132, 279–289 (2005).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  136. Shin, K. et al. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells bladder. Nature 427, 110–114 (2011).

    Article  CAS  Google Scholar 

  137. Retaux, S., Pottin, K. & Alunni, A. Shh and forebrain evolution in the blind cavefish Astyanax mexicanus. Biol. Cell 100, 139–147 (2008).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  139. Kano, S. et al. Two lamprey Hedgehog genes share non-coding regulatory sequences and expression patterns with gnathostome Hedgehogs. PLoS ONE 5, e1 3332.

    Google Scholar 

  140. Keys, D. N. et al. Recruitment of a hedgehog regulatory circuit in butterfly eyespot evolution. Science 283, 532–534 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  142. Low, J. A. & de Sauvage, F. J. Clinical experience with Hedgehog pathway inhibitors. J. Clin. Oncol. 28, 5321–5326 (2010).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Ogden, S. K. et al. G protein Gαi functions immediately downstream of Smoothened in Hedgehog signalling. Nature 456, 967–970 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  148. Zhao, Y., Tong, C. & Jiang, J. Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450, 252–258 (2007).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Corbit, K. C. et al. Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018–1021 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Kuwabara, P. E. & Labouesse, M. The sterol-sensing domain: multiple families, a unique role? Trends Genet. 18, 193–201 (2002).

    Article  CAS  PubMed  Google Scholar 

  153. Hausmann, G., von Mering, C. & Basler, K. The hedgehog signaling pathway: where did it come from? PLoS Biol. 7, e1000146 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Halbleib, J. M. & Nelson, W. J. Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev. 20, 3199–3214 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Chen, X. et al. Processing and turnover of the Hedgehog protein in the endoplasmic reticulum. J. Cell Biol. 192, 825–838 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  157. Pitsouli, C. & Perrimon, N. Developmental biology: our fly cousins' gut. Nature 454, 592–593 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to A. McMahon for his input into earlier drafts of the manuscript and to the anonymous Reviewers for their helpful suggestions for improvements. The authors would like to apologize to those authors whose work they have failed to cite owing to journal space constraints. Y.N.'s sabbatical visit to Institute of Molecular and Cell Biology was supported by a Naito Foundation Fellowship (Japan) and by the IMCB.

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Correspondence to Philip W. Ingham.

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Philip W. Ingham is a minor shareholder in Curis Inc., which is involved in the production of HH antagonists.

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Smoothened: sequence conservation and divergence across phyla (PDF 633 kb)

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Glossary

Cadherin repeats

Extracellular calcium-binding domains originally identified in the calcium-dependent adhesion proteins, cadherins.

TNFR repeats

Cysteine-rich motifs originally defined in the extracellular domain of the tumour necrosis factor receptor but also found in laminins and other receptors.

Inteins

Protein segments that can self-excise and rejoin the remaining portions of the protein with a peptide bond.

Choanoflagellates

A group of protists that possess one flagellum at some stage of their life history.

Eumetazoa

An animal sub-kingdom that includes Cnidarians, the ctenophorans and the bilaterians.

Porifera

A phylum of multicellular animals with only two cell layers, the ectoderm and the endoderm, which are separated by an acellular mesoglea. Commonly known as sponges.

Cnidarians

A simple and ancient phylum of multicellular animals, such as jelly fish or corals, found mainly in marine environments.

Palmitoylation

The covalent attachment of palmitic acid or other fatty acids to cysteine residues of proteins that promotes their association with membranes.

Imaginal discs

The undifferentiated epithelial sheets of cells that give rise to adult structures such as wings and legs.

Lipophorin

A family of high-density lipid-transporting lipoproteins found in the heamolymph of insects.

Glypicans

A family of heparan sulphate proteoglycans that are localized to the cell surface via GPI anchors.

GPI anchor

A glycolipid, glycosylphosphatidylinositol, linked to the C-terminal amino acid of proteins anchoring them to the outer leaflet of the plasma membrane.

GLI protein family

Zinc finger domain-containing transcription factors mediating HH activity, so-called because the gene encoding the founding member GLI1 is frequently amplified in glioblastoma cells.

RND proteins

A superfamily of transmembrane proteins, originally defined by bacterial proteins that function as transporters in drug resistance, legume nodulation and cell division (hence RND), but now including various eukaryotic proteins with diverse functions.

Proteasome

Large protein complex that contains proteases that regulate the concentration of particular cellular proteins and degrade misfolded proteins by proteolysis.

Deuterostomia

Animals characterized by the formation of distinct mouth and anal openings during embryonic development.

SANT1

A potent HH pathway antagonist that directly binds and inhibits the activity of both wild-type and oncogenic forms of SMO.

Protostomes

Animals the embryonic development of which is characterized by the formation of a single opening.

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Ingham, P., Nakano, Y. & Seger, C. Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet 12, 393–406 (2011). https://doi.org/10.1038/nrg2984

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