Advertisement

Sonic Hedgehog Signalling in Visceral Organ Development

Chapter
  • 478 Downloads
Part of the Molecular Biology Intelligence Unit book series (MBIU)

Abstract

The secreted signalling molecule encoded by Sonic hedgehog (Shh) has been shown to play an indispensable role in mammalian organogenesis. During embryonic development, one of the prominent sites of Shh expression is in the tubular gut endoderm and its derivatives such as the esophagus, lung, stomach and intestine. Loss of Shh function results in profound growth and patterning defects of the gastrointestinal tract and associated organs. Furthermore, misregulation of Shh signalling in human patients has been implicated in a variety of gastrointestinal tumors. In this chapter, we will discuss studies that reveal the critical roles of Shh signalling in mammalian visceral organ development and homeostasis.

Keywords

Sonic Hedgehog Glandular Stomach Pancreas Development Smooth Muscle Differentiation Zymogenic Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ingham PW, McMahon AP. Hedgehog signaling in animal development: Paradigms and principles. Genes Dev 2001; 15:3059–87.PubMedCrossRefGoogle Scholar
  2. 2.
    Bai CB, Auerbach W, Lee JS et al. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 2002; 129:4753–61.PubMedCrossRefGoogle Scholar
  3. 3.
    Motoyama J et al. Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Dev Biol 2003; 259:150–61.PubMedCrossRefGoogle Scholar
  4. 4.
    Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 2000; 100:423–34.PubMedCrossRefGoogle Scholar
  5. 5.
    Litingtung Y, Dahn RD, Li Y et al. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature 2002; 418:979–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Bai CB, Stephen D, Joyner AL. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev Cell 2004; 6:103–15.PubMedCrossRefGoogle Scholar
  7. 7.
    Chuang PT, McMahon AP. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999; 397:617–21.PubMedCrossRefGoogle Scholar
  8. 8.
    Litingtung Y, Lei L, Westphal H et al. Sonic hedgehog is essential to foregut development. Nat Genet 1998; 20:58–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Pepicelli CV, Lewis PM, McMahon AP. Sonic hedgehog regulates branching morphogenesis in the mammalian lung. Curr Biol 1998; 8:1083–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Skandalakis JE, Gray SW, Ricketts R. Embryology for surgeons. Baltimore: Williams and Wilkins, 1994.Google Scholar
  11. 11.
    Motoyama J et al. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus [see comments]. Nat Genet 1998; 20:54–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Mendelsohn C et al. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 1994; 120:2749–71.PubMedGoogle Scholar
  13. 13.
    Berman DM et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003; 425:846–51.PubMedCrossRefGoogle Scholar
  14. 14.
    Wessells NK. Mammalian lung development: Interactions in formation and morphogenesis of tracheal buds. J Exp Zool 1970; 175:455–66.PubMedCrossRefGoogle Scholar
  15. 15.
    Perl AK, Whitsett JA. Molecular mechanisms controlling lung morphogenesis. Clin Genet 1999; 56:14–27.PubMedCrossRefGoogle Scholar
  16. 16.
    Toilet J, Everett AW, Sparrow MP. Spatial and temporal distribution of nerves, ganglia, and smooth muscle during the early pseudoglandular stage of fetal mouse lung development. Dev Dyn 2001; 221:48–60.CrossRefGoogle Scholar
  17. 17.
    Bitgood MJ, McMahon AP. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev Biol 1995; 172:126–38.PubMedCrossRefGoogle Scholar
  18. 18.
    Bellusci S et al. Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis. Development 1997; 124:53–63.PubMedGoogle Scholar
  19. 19.
    Miller LA, Wert SE, Whitsett JA. Immunolocalization of sonic hedgehog (Shh) in developing mouse lung. J Histochem Cytochem 2001; 49:1593–604.PubMedGoogle Scholar
  20. 20.
    Unger S, Copland I, Tibboel D et al. Down-regulation of sonic hedgehog expression in pulmonary hypoplasia is associated with congenital diaphragmatic hernia. Am J Pathol 2003; 162:547–55.PubMedGoogle Scholar
  21. 21.
    Li Y, Zhang H, Choi SC et al. Sonic hedgehog signaling regulates Gli3 processing, mesenchymal proliferation, and differentiation during mouse lung organogenesis. Dev Biol 2004; 270:214–31.PubMedCrossRefGoogle Scholar
  22. 22.
    Chuang PT, Kawcak T, McMahon AP. Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung. Genes Dev 2003; 17:342–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Bellusci S, Grindley J, Emoto H et al. Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development 1997; 124:4867–78.PubMedGoogle Scholar
  24. 24.
    Min HS, Danilenko DM, Scully SA. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Gene Dev 1998; 12:3156–3161.PubMedCrossRefGoogle Scholar
  25. 25.
    Cardoso WV, Itoh A, Nogawa H et al. FGF-1 and FGF-7 induce distinct patterns of growth and differentiation in embryonic lung epithelium. Dev Dyn 1997; 208:398–405.PubMedCrossRefGoogle Scholar
  26. 26.
    Hogan BLM et al. Branching morphogenesis of the lung: new models for a classical problem. Cold Spring Horbor Symp Quant Biol 1997; 12:249–256.Google Scholar
  27. 27.
    Grindley JC, Bellusci S, Perkins D et al. Evidence for the involvement of the Gli gene family in embryonic mouse lung development. Dev Biol 1997; 188:337–48.PubMedCrossRefGoogle Scholar
  28. 28.
    Watkins DN et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003; 422:313–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Stewart GA et al. Expression of the developmental Sonic hedgehog (Shh) signalling pathway is up-regulated in chronic lung fibrosis and the Shh receptor patched 1 is present in circulating T lymphocytes. J Pathol 2003; 199:488–95.PubMedCrossRefGoogle Scholar
  30. 30.
    Karam SM, Li Q, Gordon JI. Gastric epithelial morphogenesis in normal and transgenic mice. Am J Physiol 1997; 272:G1209–20.PubMedGoogle Scholar
  31. 31.
    Rubin DC, Swietlicki E, Gordon JI. Use of isografts to study proliferation and differentiation programs of mouse stomach epithelia. Am J Physiol 1994; 267:G27–39.PubMedGoogle Scholar
  32. 32.
    van den Brink GR et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology 2001; 121:317–28.PubMedCrossRefGoogle Scholar
  33. 33.
    Karam SM, Leblond CP. Dynamics of epithelial cells in the corpus of the mouse stomach. III. Inward migration of neck cells followed by progressive transformation into zymogenic cells. Anat Rec 1993; 236:297–313.PubMedCrossRefGoogle Scholar
  34. 34.
    Ramalho-Santos M, Melton DA, McMahon AP. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 2000; 127:2763–72.PubMedGoogle Scholar
  35. 35.
    Motoyama J, Takabatake T, Takeshima K et al. Ptch2, a second mouse Patched gene is coexpressed with Sonic hedgehog [letter]. Nat Genet 1998; 18:104–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Beachy PA, Karhadkar SS, Berman DM. Mending and malignancy. Nature 2004; 431:402.PubMedCrossRefGoogle Scholar
  37. 37.
    Hebrok M. Hedgehog signaling in pancreas development. Mech Dev 2003; 120:45–57.PubMedCrossRefGoogle Scholar
  38. 38.
    Apelqvist A, Ahlgren U, Edlund H. Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr Biol 1997; 7:801–4.PubMedCrossRefGoogle Scholar
  39. 39.
    Hebrok M, Kim SK, Melton DA. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev 1998; 12:1705–13.PubMedCrossRefGoogle Scholar
  40. 40.
    Kim SK, Hebrok M, Melton DA. Notochord to endoderm signaling is required for pancreas development. Development 1997; 124:4243–52.PubMedGoogle Scholar
  41. 41.
    Kawahira H et al. Combined activities of hedgehog signaling inhibitors regulate pancreas development. Development 2003; 130:4871–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Kim SK, Melton DA. Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc Natl Acad Sci USA 1998; 95:13036–41.PubMedCrossRefGoogle Scholar
  43. 43.
    Hebrok M, Kim SK, St Jacques B et al. Regulation of pancreas development by hedgehog signaling. Development 2000; 127:4905–13.PubMedGoogle Scholar
  44. 44.
    Thayer SP et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003; 425:851–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Potten CS. Stem cells in gastrointestinal epithelium: Numbers, characteristics and death. Philos Trans R Soc Lond B Biol Sci 1998; 353:821–30.PubMedCrossRefGoogle Scholar
  46. 46.
    Sukegawa A et al. The concentric structure of the developing gut is regulated by Sonic hedgehog derived from endodermal epithelium. Development 2000; 127:1971–80.PubMedGoogle Scholar
  47. 47.
    Madison BB et al. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development 2005; 132:279–89.PubMedCrossRefGoogle Scholar
  48. 48.
    van den Brink GR et al. Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nat Genet 2004; 36:277–82.PubMedCrossRefGoogle Scholar
  49. 49.
    Clevers H. Wnt breakers in colon cancer. Cancer Cell 2004; 5:5–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Kirkpatrick TJ et al. Identification of a mutation in the Indian Hedgehog (IHH) gene causing brachydactyly type A1 and evidence for a third locus. J Med Genet 2003; 40:42–4.PubMedCrossRefGoogle Scholar
  51. 51.
    Mo R et al. Anorectal malformations caused by defects in sonic hedgehog signaling. Am J Pathol 2001; 159:765–74.PubMedGoogle Scholar
  52. 52.
    Sasaki Y, Iwai N, Tsuda T et al. Sonic hedgehog and bone morphogenetic protein 4 expressions in the hindgut region of murine embryos with anorectal malformations. J Pediatr Surg 2004; 39:170–3, (discussion 170–3).PubMedCrossRefGoogle Scholar
  53. 53.
    Dressier G. Tubulogenesis in the developing mammalian kidney. Trends Cell Biol 2002; 12:390–5.CrossRefGoogle Scholar
  54. 54.
    Yu J, McMahon AP, Valerius MT. Recent genetic studies of mouse kidney development. Curr Opin Genet Dev 2004; 14:550–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Schedl A, Hastie ND. Cross-talk in kidney development. Curr Opin Genet Dev 2000; 10:543–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Yu J, Carroll TJ, McMahon AP. Sonic hedgehog regulates proliferation and differentiation of mesenchymal cells in the mouse metanephric kidney. Development 2002; 129:5301–12.PubMedGoogle Scholar
  57. 57.
    Kim PC, Mo R, Hui CcC. Murine models of VACTERL syndrome: Role of sonic hedgehog signaling pathway. J Pediatr Surg 2001; 36:381–4.PubMedCrossRefGoogle Scholar
  58. 58.
    Raatikainen-Ahokas A, Hytonen M, Tenhunen A et al. BMP-4 affects the differentiation of metanephric mesenchyme and reveals an early anterior-posterior axis of the embryonic kidney. Dev Dyn 2000; 217:146–58.PubMedCrossRefGoogle Scholar
  59. 59.
    Palma V et al. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development 2005; 132:335–44.PubMedCrossRefGoogle Scholar
  60. 60.
    Machold R et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 2003; 39:937–50.PubMedCrossRefGoogle Scholar
  61. 61.
    Lai K, Kaspar BK, Gage FH et al. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 2003; 6:21–7.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

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

Personalised recommendations