Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Communicating with Hedgehogs

Nature Reviews Molecular Cell Biology volume 6, pages 306–317 (2005)Cite this article

Key Points

  • Secreted Hedgehog (Hh) signalling proteins are used in higher metazoans to control cell fate and growth during the development of a wide variety of tissues and organs. In some tissues, Hh controls the formation or persistence of precursor- or stem-cell populations.

  • Hh signal binds to, and inactivates, the Patched (Ptc) 12-transmembrane (TM) domain protein. This prevents Ptc from inhibiting the function of the 7TM protein Smoothened (Smo).

  • When Ptc is inhibited by Hh, Smo is unleashed to alter the properties of cytoplasmic protein complexes that control the proteolytic processing of the Cubitus interruptus transcription factor (which is known as Ci in Drosophila melanogaster or GLI in vertebrates). These factors are differentially active in repressing or activating target genes. ptc and other genes are activated by the Hh signal, which creates a negative-feedback loop that controls the effects of Hh.

  • Differential regulation of the transcription factors Ci and GLI gives rise to three states of target gene activity: repressed, activated or unaffected. In the latter case, Hh-independent gene regulation takes place.

  • Some components of the Hh pathway have been preserved for around half a billion years; others are recognizably related to proteins that are found in yeast and are therefore at least a billion years old. Hh signalling probably arose by adapting copies of metabolic proteins for developmental signalling.

  • Hh signalling controls growth in various tissues including the skin, cerebellum, muscle, digestive tract, pancreas and prostate. Mutations that affect Hh signal transduction components can give rise to cancer in these tissues either by inactivating a negative regulator such as PTC or by inappropriately activating a positive component such as SMO.

Abstract

Signalling by secreted Hedgehog (Hh) proteins is important for the development of many tissues and organs. Damage to components of the Hh signal-transduction pathway can lead to birth defects and cancer. The Hh proteins are distributed in tissues in a gradient, and cells respond to different thresholds of Hh with distinct responses. The cellular machinery that is responsible for the unique molecular mechanisms of Hh signal transduction has been largely conserved during metazoan evolution.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hedgehog signalling in Drosophila melanogaster.
Figure 2: Hedgehog signalling in anterior–posterior patterning of the Drosophila melanogaster wing.
Figure 3: Three states for the Hedgehog pathway, for Cubitus interruptus, and for Hedgehog target genes.
Figure 4: A model for signalling by Smo and Cos2.

Similar content being viewed by others

References

  1. Reiter, C. & Gould, G. C. Thirteen ways of looking at a hedgehog. Natural History (American Museum of Natural History, New York, 1998).

  2. Nusslein-Volhard, C. & Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801 (1980).

    CAS  PubMed  Google Scholar 

  3. Krauss, S., Concordet, J. P. & Ingham, P. W. A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell 75, 1431–1444 (1993).

    CAS  PubMed  Google Scholar 

  4. Riddle, R. D., Johnson, R. L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401–1416 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993).

    CAS  PubMed  Google Scholar 

  6. Chang, D. T. et al. Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development 120, 3339–3353 (1994).

    CAS  PubMed  Google Scholar 

  7. Roelink, H. et al. Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 76, 761–775 (1994).

    CAS  PubMed  Google Scholar 

  8. 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).

    CAS  PubMed  Google Scholar 

  9. Baron, M. H. Embryonic origins of mammalian hematopoiesis. Exp. Hematol. 31, 1160–1169 (2003).

    CAS  PubMed  Google Scholar 

  10. Machold, R. et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39, 937–950 (2003).

    CAS  PubMed  Google Scholar 

  11. Palma, V. & Ruiz i Altaba, A. Hedgehog–GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 131, 337–345 (2004).

    CAS  PubMed  Google Scholar 

  12. Adolphe, C. et al. An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development 131, 5009–5019 (2004).

    CAS  PubMed  Google Scholar 

  13. Maye, P. et al. Hedgehog signaling is required for the differentiation of ES cells into neurectoderm. Dev. Biol. 265, 276–290 (2004).

    CAS  PubMed  Google Scholar 

  14. Pasca di Magliano, M. & Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nature Rev. Cancer 3, 903–911 (2003).

    Google Scholar 

  15. Lum, L. & Beachy, P. A. The Hedgehog response network: sensors, switches, and routers. Science 304, 1755–1759 (2004).

    CAS  PubMed  Google Scholar 

  16. Nusse, R. Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface. Development 130, 5297–5305 (2003).

    CAS  PubMed  Google Scholar 

  17. Stegman, M. A. et al. The Kinesin-related protein Costal2 associates with membranes in a Hedgehog-sensitive, Smoothened-independent manner. J. Biol. Chem. 279, 7064–7071 (2004).

    CAS  PubMed  Google Scholar 

  18. 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).

    CAS  PubMed  Google Scholar 

  19. 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).

    CAS  PubMed  Google Scholar 

  20. Zhang, W. et al. Hedgehog-regulated costal2-kinase complexes control phosphorylation and proteolytic processing of cubitus interruptus. Dev. Cell 8, 267–278 (2005). This paper shows how the kinesin-related protein Cos2 assembles a set of kinases that control Hh signalling by processing the transcription factor Ci.

    CAS  PubMed  Google Scholar 

  21. Jiang, J. & Struhl, G. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391, 493–496 (1998).

    CAS  PubMed  Google Scholar 

  22. Dai, P., Akimaru, H. & Ishii, S. A hedgehog-responsive region in the Drosophila wing disc is defined by debra-mediated ubiquitination and lysosomal degradation of Ci. Dev. Cell 4, 917–928 (2003).

    CAS  PubMed  Google Scholar 

  23. 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). This is one of several papers (see also references 106 – 108 ) that connected the membrane protein Smo directly to the cytoplasmic kinesin-related protein Cos2, thereby bridging membrane events with the cytoplasmic protein complex.

    CAS  PubMed  Google Scholar 

  24. Methot, N. & Basler, K. Suppressor of Fused opposes Hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development 127, 4001–4210 (2000).

    CAS  PubMed  Google Scholar 

  25. Cheng, S. Y. & Bishop, J. M. Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18–mSin3 corepressor complex. Proc. Natl Acad. Sci. USA 99, 5442–5447 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Merchant, M. et al. Suppressor of fused regulates Gli activity through a dual binding mechanism. Mol. Cell. Biol. 24, 8627–8641 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Jia, J., Tong, C., Wang, B., Luo, L. & Jiang, J. Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase 1. Nature 432, 1045–1050 (2005).

    Google Scholar 

  28. 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).

    CAS  PubMed  Google Scholar 

  29. Zhang, C., Williams, E. H., Guo, Y., Lum, L. & Beachy, P. A. Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc. Natl Acad. Sci USA 101, 17900–17907 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  31. Chen, C. H. et al. Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression. Cell 98, 305–316 (1999). Hh proteins are covalently joined to cholesterol at the C terminus and then to a palmitoyl group at the N terminus during their biosynthesis, which gives rise to a very greasy molecule. This paper reports an analysis of the importance of palmitoylation.

    CAS  PubMed  Google Scholar 

  32. Kalderon, D. Transducing the hedgehog signal. Cell 103, 371–374 (2000).

    CAS  PubMed  Google Scholar 

  33. Lee, J. D., Amanai, K., Shearn, A. & Treisman, J. E. The ubiquitin ligase Hyperplastic discs negatively regulates hedgehog and decapentaplegic expression by independent mechanisms. Development 129, 5697–5706 (2002).

    CAS  PubMed  Google Scholar 

  34. Ou, C. Y., Lin, Y. F., Chen, Y. J. & Chien, C. T. Distinct protein degradation mechanisms mediated by Cul1 and Cul3 controlling Ci stability in Drosophila eye development. Genes Dev. 16, 2403–2414 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Rahnama, F., Toftgard, R. & Zaphiropoulos, P. G. Distinct roles of PTCH2 splice variants in Hedgehog signalling. Biochem. J. 378, 325–334 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kogerman, P. et al. Mammalian suppressor-of-fused modulates nuclear–cytoplasmic shuttling of Gli-1. Nature Cell Biol. 1, 312–319 (1999).

    CAS  PubMed  Google Scholar 

  37. Paces-Fessy, M., Boucher, D., Petit, E., Paute-Briand, S. & Blanchet-Tournier, M. F. The negative regulator of Gli, Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins. Biochem. J. 378, 353–362 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Tay, S. Y., Ingham, P. W. & Roy, S. A homologue of the Drosophila kinesin-like protein Costal2 regulates Hedgehog signal transduction in the vertebrate embryo. Development 132, 625–634 (2005).

    CAS  PubMed  Google Scholar 

  39. Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003). This paper contains the startling genetic evidence that proteins that transport substances within flagella and cilia are important for Hh signal transduction.

    CAS  PubMed  Google Scholar 

  40. Callahan, C. A. et al. MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription. Genes Dev. 18, 2724–2729 (2004). One of the newest components of Hh signalling, MIM, is a protein that binds to actin and regulates GLI activity.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. McCarthy, R. A., Barth, J. L., Chintalapudi, M. R., Knaak, C. & Argraves, W. S. Megalin functions as an endocytic sonic hedgehog receptor. J. Biol. Chem. 277, 25660–25667 (2002).

    CAS  PubMed  Google Scholar 

  42. Wolff, C. et al. iguana encodes a novel zinc-finger protein with coiled-coil domains essential for Hedgehog signal transduction in the zebrafish embryo. Genes Dev. 18, 1565–1576 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sekimizu, K. et al. The zebrafish iguana locus encodes Dzip1, a novel zinc-finger protein required for proper regulation of Hedgehog signaling. Development 131, 2521–2532 (2004).

    CAS  PubMed  Google Scholar 

  44. Bulgakov, O. V., Eggenschwiler, J. T., Hong, D. H., Anderson, K. V. & Li, T. FKBP8 is a negative regulator of mouse sonic hedgehog signaling in neural tissues. Development 131, 2149–2159 (2004).

    CAS  PubMed  Google Scholar 

  45. Izraeli, S. et al. Genetic evidence that Sil is required for the Sonic Hedgehog response pathway. Genesis 31, 72–77 (2001).

    CAS  PubMed  Google Scholar 

  46. Eggenschwiler, J. T., Espinoza, E. & Anderson, K. V. Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412, 194–198 (2001). A search for early mouse mutants led to the finding that Rab23 was a gene that was necessary for neuralation owing to its involvement in Hh signalling.

    CAS  PubMed  Google Scholar 

  47. Glise, B. et al. Shifted, the Drosophila ortholog of wnt inhibitory factor-1, controls the distribution and movement of hedgehog. Dev. Cell 8, 255–266 (2005).

    CAS  PubMed  Google Scholar 

  48. Gorfinkiel, N., Sierra, J., Callejo, A., Ibanez, C. & Guerrero, I. The Drosophila ortholog of the human wnt inhibitor factor shifted controls the diffusion of lipid-modified hedgehog. Dev. Cell 8, 241–253 (2005).

    CAS  PubMed  Google Scholar 

  49. Han, C., Belenkaya, T. Y., Wang, B. & Lin, X. Drosophila glypicans control the cell-to-cell movement of Hedgehog by a dynamin-independent process. Development 131, 601–611 (2004).

    CAS  PubMed  Google Scholar 

  50. Chuang, P. T. & McMahon, A. P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397, 617–621 (1999).

    CAS  PubMed  Google Scholar 

  51. Inaki, M., Kojima, T., Ueda, R. & Saigo, K. Requirements of high levels of Hedgehog signaling activity for medial-region cell fate determination in Drosophila legs: identification of pxb, a putative Hedgehog signaling attenuator gene repressed along the anterior–posterior compartment boundary. Mech. Dev. 116, 3–18 (2002).

    CAS  PubMed  Google Scholar 

  52. Mullor, J. L. & Guerrero, I. A gain-of-function mutant of patched dissects different responses to the hedgehog gradient. Dev. Biol. 228, 211–224 (2000).

    CAS  PubMed  Google Scholar 

  53. Strigini, M. & Cohen, S. M. A Hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing. Development 124, 4697–4705 (1997).

    CAS  PubMed  Google Scholar 

  54. Muller, B. & Basler, K. The repressor and activator forms of Cubitus interruptus control Hedgehog target genes through common generic Gli-binding sites. Development 127, 2999–3007 (2000).

    CAS  PubMed  Google Scholar 

  55. Methot, N. & Basler, K. Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell 96, 819–831 (1999).

    CAS  PubMed  Google Scholar 

  56. 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). This paper reports the most rigorous genetic study of the GLI proteins so far, which are the transcriptional regulators that are controlled by Hh signalling.

    CAS  PubMed  Google Scholar 

  57. Lei, Q., Zelman, A. K., Kuang, E., Li, S. & Matise, M. P. Transduction of graded Hedgehog signaling by a combination of Gli2 and Gli3 activator functions in the developing spinal cord. Development 131, 3593–3604 (2004).

    CAS  PubMed  Google Scholar 

  58. Wang, Q. T. & Holmgren, R. A. The subcellular localization and activity of Drosophila cubitus interruptus are regulated at multiple levels. Development 126, 5097–5106 (1999).

    CAS  PubMed  Google Scholar 

  59. Mann, R. K. & Beachy, P. A. Novel lipid modifications of secreted protein signals. Annu. Rev. Biochem. 73, 891–923 (2004).

    CAS  PubMed  Google Scholar 

  60. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  64. Tian, H., Tenzen, T. & McMahon, A. P. Dose dependency of Disp1 and genetic interaction between Disp1 and other hedgehog signaling components in the mouse. Development 131, 4021–4033 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  66. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Feng, J. et al. Synergistic and antagonistic roles of the Sonic hedgehog N- and C-terminal lipids. Development 131, 4357–4370 (2004).

    CAS  PubMed  Google Scholar 

  68. Denef, N., Neubuser, D., Perez, L. & Cohen, S. M. Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell 102, 521–531 (2000).

    CAS  PubMed  Google Scholar 

  69. Incardona, J. P., Gruenberg, J. & Roelink, H. Sonic hedgehog induces the segregation of Patched and Smoothened in endosomes. Curr. Biol. 12, 893–895 (2002).

    Google Scholar 

  70. Gallet, A. & Therond, P. P. Temporal modulation of the Hedgehog morphogen gradient by a patched-dependent targeting to lysosomal compartment. Dev. Biol. 277, 51–62 (2005). A study of the fate of Hh protein after it enters the cell.

    CAS  PubMed  Google Scholar 

  71. Torroja, C., Gorfinkiel, N. & Guerrero, I. Patched controls the Hedgehog gradient by endocytosis in a dynamin-dependent manner, but this internalization does not play a major role in signal transduction. Development 131, 2395–2408 (2004). This study of the intracellular locations and movements of Hh signal transduction components included the careful analysis of which events are important for Hh signalling.

    CAS  PubMed  Google Scholar 

  72. Nybakken, K. & Perrimon, N. Hedgehog signal transduction: recent findings. Curr. Opin. Genet. Dev. 12, 503–511 (2002).

    CAS  PubMed  Google Scholar 

  73. Desbordes, S. C. & Sanson, B. The glypican Dally-like is required for Hedgehog signalling in the embryonic epidermis of Drosophila. Development 130, 6245–6255 (2003).

    CAS  PubMed  Google Scholar 

  74. Bornemann, D. J., Duncan, J. E., Staatz, W., Selleck, S. & Warrior, R. Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways. Development 131, 1927–1938 (2004). The mystery of how Hh proteins move between cells remains unsolved, but this paper provides evidence that heparan-sulphate proteoglycans are important for the movement of Hh and other signalling molecules in D. melanogaster.

    CAS  PubMed  Google Scholar 

  75. Koziel, L., Kunath, M., Kelly, O. G. & Vortkamp, A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev. Cell 6, 801–813 (2004).

    CAS  PubMed  Google Scholar 

  76. Chen, Y. & Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 87, 553–563 (1996).

    CAS  PubMed  Google Scholar 

  77. Ioannou, Y. A. Multidrug permeases and subcellular cholesterol transport. Nature Rev. Mol. Cell Biol. 2, 657–668 (2001).

    CAS  Google Scholar 

  78. Taipale, J., Cooper, M. K., Maiti, T. & Beachy, P. A. Patched acts catalytically to suppress the activity of Smoothened. Nature 418, 892–897 (2002).

    CAS  PubMed  Google Scholar 

  79. Ohgami, N. et al. Binding between the Niemann–Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain. Proc. Natl Acad. Sci. USA 101, 12473–12478 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Radhakrishnan, A., Sun, L. P., Kwon, H. J., Brown, M. S. & Goldstein, J. L. Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Mol. Cell 15, 259–268 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  82. Martin, V., Carrillo, G., Torroja, C. & Guerrero, I. The sterol-sensing domain of Patched protein seems to control Smoothened activity through Patched vesicular trafficking. Curr. Biol. 11, 601–607 (2001).

    CAS  PubMed  Google Scholar 

  83. Strutt, H. et al. Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation. Curr. Biol. 11, 608–613 (2001).

    CAS  PubMed  Google Scholar 

  84. Johnson, R. L., Zhou, L. & Bailey, E. C. Distinct consequences of sterol sensor mutations in Drosophila and mouse patched homologs. Dev. Biol. 242, 224–235 (2002).

    CAS  PubMed  Google Scholar 

  85. Ko, D. C., Gordon, M. D., Jin, J. Y. & Scott, M. P. Dynamic movements of organelles containing Niemann–Pick C1 protein: NPC1 involvement in late endocytic events. Mol. Biol. Cell 12, 601–614 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Davies, J. P., Chen, F. W. & Ioannou, Y. A. Transmembrane molecular pump activity of Niemann–Pick C1 protein. Science 290, 2295–2298 (2000).

    CAS  PubMed  Google Scholar 

  87. Casali, A. & Struhl, G. Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein. Nature 431, 76–80 (2004).

    CAS  PubMed  Google Scholar 

  88. Hooper, J. E. Smoothened translates Hedgehog levels into distinct responses. Development 130, 3951–3963 (2003). This paper shows different, separable aspects of Smo function using chimeric constructs of Smo and its closest relative Fz, a Wnt receptor. A chimaera that consists of Fz on the outside and Smo on the inside of the cell responds to Wnt but triggers Hh signal transduction.

    CAS  PubMed  Google Scholar 

  89. Stone, D. M. et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384, 129–134 (1996).

    CAS  PubMed  Google Scholar 

  90. Johnson, R. L., Milenkovic, L. & Scott, M. P. In vivo functions of the patched protein: requirement of the C terminus for target gene inactivation but not Hedgehog sequestration. Mol. Cell 6, 467–478 (2000).

    CAS  PubMed  Google Scholar 

  91. Zhu, A. J., Zheng, L., Suyama, K. & Scott, M. P. Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction. Genes Dev. 17, 1240–1252 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005–1009 (2000).

    CAS  PubMed  Google Scholar 

  93. Chen, J. K., Taipale, J., Young, K. E., Maiti, T. & Beachy, P. A. Small molecule modulation of Smoothened activity. Proc. Natl Acad. Sci. USA 99, 14071–14076 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Frank-Kamenetsky, M. et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol. 1, 10 (2002).

    PubMed  PubMed Central  Google Scholar 

  96. Evans, T. M., Ferguson, C., Wainwright, B. J., Parton, R. G. & Wicking, C. Rab23, a negative regulator of Hedgehog signaling, localizes to the plasma membrane and the endocytic pathway. Traffic 4, 869–884 (2003).

    CAS  PubMed  Google Scholar 

  97. Nakano, Y. et al. Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila. Mech. Dev. 121, 507–518 (2004).

    CAS  PubMed  Google Scholar 

  98. Eggenschwiler, J. T. & Anderson, K. V. Dorsal and lateral fates in the mouse neural tube require the cell-autonomous activity of the open brain gene. Dev. Biol. 227, 648–60 (2000).

    CAS  PubMed  Google Scholar 

  99. Chen, W. et al. Activity-dependent internalization of smoothened mediated by β-arrestin 2 and GRK2. Science 306, 2257–2260 (2004).

    CAS  PubMed  Google Scholar 

  100. Wilbanks, A. M. et al. β-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway. Science 306, 2264–2267 (2004).

    CAS  PubMed  Google Scholar 

  101. Pitcher, J. A., Freedman, N. J. & Lefkowitz, R. J. G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653–6592 (1998).

    CAS  PubMed  Google Scholar 

  102. 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).

    CAS  PubMed  Google Scholar 

  103. DeCamp, D. L., Thompson, T. M., de Sauvage, F. J. & Lerner, M. R. Smoothened activates Gαi-mediated signaling in frog melanophores. J. Biol. Chem. 275, 26322–26327 (2000).

    CAS  PubMed  Google Scholar 

  104. Kasai, K. et al. The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling. Genes Cells 9, 49–58 (2004).

    CAS  PubMed  Google Scholar 

  105. Lum, L. et al. Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299, 2039–2045 (2003). A large-scale screen that identified new Hh signal transduction components in D. melanogaster cultured cells, using RNAi.

    CAS  PubMed  Google Scholar 

  106. Ogden, S. K. et al. Identification of a functional interaction between the transmembrane protein Smoothened and the kinesin-related protein Costal2. Curr. Biol. 13, 1998–2003 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 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).

    CAS  PubMed  Google Scholar 

  108. Jia, J., Tong, C. & Jiang, J. Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail. Genes Dev. 17, 2709–2720 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Ho, K. S., Suyama, K., Fish, M. & Scott, M. P. Differential regulation of Hedgehog target gene transcription by Costal2 and Suppressor of Fused. Development 132, 1401–1412 (2005).

    CAS  PubMed  Google Scholar 

  110. Mahadevan, L. & Matsudaira, P. Motility powered by supramolecular springs and ratchets. Science 288, 95–100 (2000).

    CAS  PubMed  Google Scholar 

  111. Kalderon, D. Similarities between the Hedgehog and Wnt signaling pathways. Trends Cell Biol. 12, 523–531 (2002).

    CAS  PubMed  Google Scholar 

  112. Hall, T. M., Porter, J. A., Beachy, P. A. & Leahy, D. J. A potential catalytic site revealed by the 1.7-Å crystal structure of the amino-terminal signalling domain of Sonic hedgehog. Nature 378, 212–216 (1995).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  114. Hall, T. M. et al. Crystal structure of a Hedgehog autoprocessing domain: homology between Hedgehog and self-splicing proteins. Cell 91, 85–97 (1997).

    CAS  PubMed  Google Scholar 

  115. Berman, D. M. et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297, 1559–1561 (2002).

    CAS  PubMed  Google Scholar 

  116. Romer, J. T. et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1+/− p53−/− mice. Cancer Cell 6, 229–240 (2004). This paper analyses the effects of inhibitors of SMO on the growth of medulloblastomas, which are cranial tumours caused by the inadequate inhibition of Hh target gene activities. The results show both prevention of tumour formation and regression of pre-existing tumours.

    CAS  PubMed  Google Scholar 

  117. Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20–29 (2000).

    CAS  PubMed  Google Scholar 

  118. Shenoy, S. K. & Lefkowitz, R. J. Receptor-specific ubiquitination of β-arrestin directs assembly and targeting of 7TM receptor-signalosomes. J. Biol. Chem. 7 Feb 2005 [epub ahead of print].

  119. Takei, Y., Ozawa, Y., Sato, M., Watanabe, A. & Tabata, T. Three Drosophila EXT genes shape morphogen gradients through synthesis of heparan sulfate proteoglycans. Development 131, 73–82 (2004).

    CAS  PubMed  Google Scholar 

  120. Meng, X. et al. Suppressor of fused negatively regulates β-catenin signaling. J. Biol. Chem. 276, 40113–40119 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank our many colleagues for sharing their manuscripts in press, and apologize to those whose work has gone unmentioned owing to space limitations. We gratefully acknowledge support to our laboratories from Howard Hughes Medical Institute and the National Institutes of Health, and the contributions made by current and past collaborators and members of our laboratories.

Author information

Authors and Affiliations

  1. Department of Cell and Developmental Biology, University of Colorado School of Medicine, 12801 East 17th Avenue, Box 8018, Aurora, 80045, Colorado, USA

    Joan E. Hooper

  2. Departments of Developmental Biology, Genetics and Bioengineering, Howard Hughes Medical Institute, Clark Center W252, 318 Campus Drive, Stanford University School of Medicine, Stanford, 94305-5439, California, USA

    Matthew P. Scott

Authors
  1. Joan E. Hooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew P. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

Matthew P. Scott is a scientific advisor to CURIS, Inc., a company that is developing drugs that work through the Hedgehog pathway.

Related links

Related links

DATABASES

Entrez Gene

Dhh

Gli1

Gli2

Gli3

Ihh

KIF7

Ptc1

Ptc2

Shh

Flybase

Ci

Cos2

Dlp

dpp

hh

Shf

Smo

Sufu

Ptc

Slmb

Swiss-Prot

KIF3a

NPC1

SMO

WIF

FURTHER INFORMATION

The Wnt homepage

Glossary

ORTHOLOGUES

Functionally related genes with extensive sequence similarity, which indicates a common ancestor. Orthologues are often used to indicate the most closely related members of larger gene families in different species.

HOLOPROSENCEPHALY

An inborn cranial defect, which is characterized by failure to separate midline structures in the brain and face.

KINESINS

A family of microtubule-based motors, which typically move towards the plus ends of microtubules.

F-BOX PROTEIN

A component of the machinery for the ubiquitin-dependent degradation of proteins. F-box proteins recognize specific substrates and, with the help of other subunits of the E3 ubiquitin-ligase complex, deliver them to the E2 ubiquitin-conjugating enzyme.

SCF UBIQUITIN E3 LIGASE

An E3 ubiquitin ligase that contains SKP1, a member of the cullin family (CUL1), and an F-box-containing protein (SKP2), as well as a RING-finger-containing protein (ROC1/RBX1).

MEDULLOBLASTOMA

A brain tumour that consists of cells that resemble the undifferentiated cells of the primitive medullary tube.

PROTEASOME

A large protein complex that is responsible for degrading intracellular proteins that have been targeted for destruction, usually by the addition of ubiquitin polymers.

HEPARAN-SULPHATE PROTEOGLYCAN

A protein that is modified by heparan-sulphate side chains.

WNT PROTEINS

A family of highly conserved secreted signalling molecules that regulate cell–cell interactions during embryogenesis and in adult tissues.

MORPHOGEN

A substance that is active in pattern formation, the spatial concentration or activity of which varies, and to which cells respond differently at different threshold concentrations.

NEURAL TUBE

A cylindrical structure that runs through the midline of the embryo; it expands in the head to form the brain and in the trunk to form the spinal cord.

AVIDITY

The strength of binding, usually of multiple aggregated ligand–receptor complexes.

EXTRACELLULAR MATRIX

(ECM). The complex, multi-molecular material that surrounds cells. The ECM comprises a scaffold on which tissues are organized, it provides cellular microenvironments and it regulates various cellular functions.

SEVEN-TRANSMEMBRANE RECEPTORS

(7TMs). A class of receptors that contains seven membrane-spanning helices and that usually transmits signals to the inside of a cell by activating heterotrimeric G proteins.

FLOOR PLATE

The neural tube has been divided into different regions: the ventral cells, which lie closest to the midline, constitute the floor plate; the dorsal cells, which lie closest to the midline, constitute the roof plate.

NOTOCHORD

A rod of mesodermal cells in the dorsal midline beneath the neural tube. It is the main characteristic of chordates.

TERATOGENS

Agents that cause the malformation of a developing fetus; for example, chemicals, viruses and ionizing radiation.

DOMINANT-NEGATIVE PROTEIN

A defective protein that inhibits the function of normal proteins often by competing with normal proteins for interacting molecules through retained interaction capabilities.

HETEROTRIMERIC G PROTEIN

A protein complex composed of three proteins (Gα, Gβ and Gγ). Whereas Gβ and Gγ form a tight complex, Gα is part of the complex in its inactive, GDP-bound, form, but dissociates from the complex in its active, GTP-bound, form. Both Gα and Gβγ can transmit downstream signals after activation.

MELANOPHORES

Pigmented cells, present in fish and other vertebrates, in which pigment granules rapidly disperse or aggregate by moving along the microtubules that radiate from the centre of the cells. This causes the skin to darken or lighten, respectively.

RNA INTERFERENCE

(RNAi). A form of post-transcriptional gene silencing in which expression or transfection of double-stranded RNA induces degradation — by nucleases — of the homologous endogenous transcripts. This mimics the effect of the reduction, or loss, of gene activity.

METAZOANS

Refers to the kingdom Animalia (animals) that comprises roughly 35 phyla of multicellular organisms.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hooper, J., Scott, M. Communicating with Hedgehogs. Nat Rev Mol Cell Biol 6, 306–317 (2005). https://doi.org/10.1038/nrm1622

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1622

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing