Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Sonic Hedgehog (Shh)

  • Kaitlyn RyanEmail author
  • Chin Chiang
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_102

Historical Background

The Hedgehog (Hh) family of secreted proteins plays an essential role in metazoan development, and defects in the Hh pathway lead to congenital abnormalities such as holoprosencephaly and certain forms of cancer. The importance of Hh during embryogenesis was first discovered in a genetic screen for mutations disrupting larval patterning in Drosophila melanogaster by Nusslein-Volhard and Wieschaus in 1980 (Varjosalo and Taipale 2008). Unlike Drosophila, which harbors a single Hh gene, the mammalian genome encodes three Hh ligands: Dessert Hedgehog (Dhh), Indian Hedgehog (Ihh), and Sonic Hedgehog (Shh), all of which activate the vertebrate Hh pathway in a similar manner. Shh is the most widely expressed of these ligands, and much of what is known about vertebrate Hh signaling stems from studies on Shh. Though similar in many ways to the DrosophilaHh pathway, several features of vertebrate Hh signaling make it unique. Perhaps the most striking divergence is in the...

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  1. Allen BL, Song JY, Izzi L, Althaus IW, Kang JS, Charron F, et al. Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev Cell. 2011;20(6):775–87.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Barakat MT, Humke EW, Scott MP. Learning from Jekyll to control Hyde: hedgehog signaling in development and cancer. Trends Mol Med. 2010;16(8):337–48.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Beachy PA, Hymowitz SG, Lazarus RA, Leahy DJ, Siebold C. Interactions between hedgehog proteins and their binding partners come into view. Genes Dev. 2010;24(18):2001–12.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Caspary T, Garcia-Garcia MJ, Huangfu D, Eggenschwiler JT, Wyler MR, Rakeman AS, et al. Mouse dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr Biol. 2002;12(18):1628–32.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Chen MH, Li YJ, Kawakami T, Xu SM, Chuang PT. Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev. 2004;18(6):641–59.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Chen X, Tukachinsky H, Huang CH, Jao C, Chu YR, Tang HY, et al. Processing and turnover of the hedgehog protein in the endoplasmic reticulum. J Cell Biol. 2011;192(5):825–38.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Cheung HO, Zhang X, Ribeiro A, Mo R, Makino S, Puviindran V, et al. The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci Signal. 2009;2(76):ra29.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Dierker T, Dreier R, Petersen A, Bordych C, Grobe K. Heparan sulfate-modulated, metalloprotease-mediated sonic hedgehog release from producing cells. J Biol Chem. 2009;284(12):8013–22.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen JW, Phamluong K, et al. The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol. 2009;19(15):1320–6.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Goetz SC, Anderson KV. The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet. 2010;11(5):331–44.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Guerrero I, Chiang C. A conserved mechanism of Hedgehog gradient formation by lipid modifications. Trends Cell Biol. 2007;17(1):1–5.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R. The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins. Genes Dev. 2010;24(7):670–82.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Ingham PW, Nakano Y, Seger C. Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet. 2011;12(6):393–406.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Izzi L, Levesque M, Morin S, Laniel D, Wilkes BC, Mille F, et al. Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. Dev Cell. 2011;20(6):788–801.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell. 2008;15(6):801–12.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Kawakami T, Kawcak T, Li YJ, Zhang W, Hu Y, Chuang PT. Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development. 2002;129(24):5753–65.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Lewis PM, Dunn MP, McMahon JA, Logan M, Martin JF, St-Jacques B, et al. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell. 2001;105(5):599–612.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Li Y, Zhang H, Litingtung Y, Chiang C. Cholesterol modification restricts the spread of Shh gradient in the limb bud. Proc Natl Acad Sci USA. 2006;103(17):6548–53.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Liem Jr KF, He M, Ocbina PJ, Anderson KV. Mouse Kif7/Costal2 is a cilia-associated protein that regulates sonic hedgehog signaling. Proc Natl Acad Sci USA. 2009;106(32):13377–82.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Ma Y, Erkner A, Gong R, Yao S, Taipale J, Basler K, et al. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell. 2002;111(1):63–75.PubMedPubMedCentralCrossRefGoogle Scholar
  21. McMahon AP, Ingham PW, Tabin CJ. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol. 2003;53:1–114.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Milenkovic L, Scott MP, Rohatgi R. Lateral transport of smoothened from the plasma membrane to the membrane of the cilium. J Cell Biol. 2009;187(3):365–74.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Ng JM, Curran T. The Hedgehog’s tale: developing strategies for targeting cancer. Nat Rev Cancer. 2011;11(7):493–501.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Ocbina PJ, Eggenschwiler JT, Moskowitz I, Anderson KV. Complex interactions between genes controlling trafficking in primary cilia. Nat Genet. 2011;43(6):547–53.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Ohlig S, Farshi P, Pickhinke U, van den Boom J, Hoing S, Jakuschev S, et al. Sonic hedgehog shedding results in functional activation of the solubilized protein. Dev Cell. 2011;20(6):764–74.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Tukachinsky H, Lopez LV, Salic A. A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J Cell Biol. 2010;191(2):415–28.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22(18):2454–72.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Wang C, Pan Y, Wang B. Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development. 2010;137(12):2001–9.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Wilson CW, Chuang PT. Mechanism and evolution of cytosolic Hedgehog signal transduction. Development. 2010;137(13):2079–94.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455(7211):406–10.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Cell and Developmental BiologyVanderbilt University Medical CenterNashvilleUSA