The Role of Sonic Hedgehog Signalling in Craniofacial Development

Part of the Molecular Biology Intelligence Unit book series (MBIU)


The unique characteristics of our face contribute to individuality, distinguishing us from other human beings as well as other species. This has led to the face being thought of as an isolated entity, in terms of both embryonic development and postnatal physical characteristics. The artistic intricacy of facial features is a reflection of multiple sophisticated spatial and temporal developmental events and interactions, not only within tissues that give rise to the face but also between these and other tissues such as the brain. The culmination of such interactions transforms planar tissue into readily recognizable complex three-dimensional structures with unique characteristics that we identify as our face. Complexity not simplicity, and interactions not seclusion, are the axioms in craniofacial development.


Neural Crest Chick Embryo Neural Crest Cell Sonic Hedgehog Palatal Shelf 
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  1. 1.
    Couly G, Le Douarin NM. Head morphogenesis in embryonic avian chimeras: Evidence for a segmental pattern in the ectoderm corresponding to the neuromeres. Development 1990; 108:543–558.PubMedGoogle Scholar
  2. 2.
    Wilson SW, Houart C. Early steps in the development of the forebrain. Dev Cell 2004; 6:167–181.PubMedCrossRefGoogle Scholar
  3. 3.
    Schuurmans C, Guillemot F. Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr Opin Neurobiol 2002; 12:26–34.PubMedCrossRefGoogle Scholar
  4. 4.
    Meulemans D, Bronner-Fraser M. Gene-regulatory interactions in neural crest evolution and development. Dev Cell 2004; 7:291–299.PubMedCrossRefGoogle Scholar
  5. 5.
    Etchevers HC, Vincent C, Le Douarin NM et al. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 2001; 128:1059–1068.PubMedGoogle Scholar
  6. 6.
    Noden DM. Origins and patterning of craniofacial mesenchymal tissues. J Craniofac Genet Dev Biol Suppl 1986; 2:15–31.PubMedGoogle Scholar
  7. 7.
    Helms JA, Schneider RA. Cranial skeletal biology. Nature 2003; 423:326–331.PubMedCrossRefGoogle Scholar
  8. 8.
    Le Douarin NM, Dupin E. Multipotentiality of the neural crest. Curr Opin Genet Dev 2003; 13:529–536.PubMedCrossRefGoogle Scholar
  9. 9.
    Trainor PA, Melton KR, Manzanares M. Origins and plasticity of neural crest cells and their roles in jaw and craniofacial evolution. Int J Dev Biol 2003; 47:541–553.PubMedGoogle Scholar
  10. 10.
    Kulesa P, Ellies DL, Trainor PA. Comparative analysis of neural crest cell death, migration, and function during vertebrate embryogenesis. Dev Dyn 2004; 229:14–29.PubMedCrossRefGoogle Scholar
  11. 11.
    Le Douarin NM, Creuzet S, Couly G et al. Neural crest cell plasticity and its limits. Development 2004; 131:4637–4650.PubMedCrossRefGoogle Scholar
  12. 12.
    Helms JA, Cordero D, Tapadia MD. New insights into craniofacial morphogenesis. Development 2005; 132:851–861.PubMedCrossRefGoogle Scholar
  13. 13.
    Noden DM. The role of the neural crest in patterning of avian cranial skeletal, connective, and muscle tissues. Dev Biol 1983; 96:144–165.PubMedCrossRefGoogle Scholar
  14. 14.
    Couly G, Grapin-Botton A, Coltey P et al. Determination of the identity of the derivatives of the cephalic neural crest: Incompatibility between Hox gene expression and lower jaw development. Development 1998; 125:3445–3459.PubMedGoogle Scholar
  15. 15.
    Schneider RA, Helms JA. The cellular and molecular origins of beak morphology. Science 2003; 299:565–568.PubMedCrossRefGoogle Scholar
  16. 16.
    Trainor PA, Krumlauf R. Patterning the cranial neural crest: Hindbrain segmentation and Hox gene plasticity. Nat Rev Neurosci 2000; 1:116–124.PubMedCrossRefGoogle Scholar
  17. 17.
    Couly G, Creuzet S, Bennaceur S et al. Interactions between Hox-negative cephalic neural crest cells and the foregut endoderm in patterning the facial skeleton in the vertebrate head. Development 2002; 129:1061–1073.PubMedGoogle Scholar
  18. 18.
    Trainor PA, Ariza-McNaughton L, Krumlauf R. Role of the isthmus and FGFs in resolving the paradox of neural crest plasticity and prepatterning. Science 2002; 295:1288–1291.PubMedCrossRefGoogle Scholar
  19. 19.
    Hu D, Marcucio RS, Helms JA. A zone of frontonasal ectoderm regulates patterning and growth in the face. Development 2003; 130:1749–1758.PubMedCrossRefGoogle Scholar
  20. 20.
    Trumpp A, Depew MJ, Rubenstein JL et al. Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch. Genes Dev 1999; 13:3136–3148.PubMedCrossRefGoogle Scholar
  21. 21.
    Creuzet S, Schuler B, Couly G et al. Reciprocal relationships between FgfB and neural crest cells in facial and forebrain development. Proc Natl Acad Sci USA 2004; 101:4843–4847.PubMedCrossRefGoogle Scholar
  22. 22.
    DeMyer W, Zeman W, Palmer CG. The face predicts the brain: Diagnostic significance of median facial anomalies for holoprosencephaly (arhinencephaly). Pediatrics 1964:256–263.Google Scholar
  23. 23.
    Schneider RA, Hu D, Rubenstein JL et al. Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH. Development 2001; 128:2755–2767.PubMedGoogle Scholar
  24. 24.
    Cordero D, Marcucio R, Hu D et al. Temporal perturbations in sonic hedgehog signaling elicit the spectrum of holoprosencephaly phenotypes. J Clin Invest 2004; 114:485–494.PubMedGoogle Scholar
  25. 25.
    Marcucio RS, Cordero DR, Hu D et al. Molecular interactions coordinating the development of the forebrain and face. Dev Biol 2005; 284:48–61.PubMedCrossRefGoogle Scholar
  26. 26.
    Helms JA, Kim CH, Hu D et al. Sonic hedgehog participates in craniofacial morphogenesis and is down-regulated by teratogenic doses of retinoic acid. Dev Biol 1997; 187:25–35.PubMedCrossRefGoogle Scholar
  27. 27.
    Richman JM, Herbert M, Matovinovic E et al. Effect of fibroblast growth factors on outgrowth of facial mesenchyme. Dev Bioi 1997; 189:135–147.CrossRefGoogle Scholar
  28. 28.
    Francis-West PH, Tatla T, Brickell PM. Expression patterns of the bone morphogenetic protein genes Bmp-4 and Bmp-2 in the developing chick face suggest a role in outgrowth of the primordia. Dev Dyn 1994; 201:168–178.PubMedGoogle Scholar
  29. 29.
    Barlow AJ, Francis-West PH. Ectopic application of recombinant BMP-2 and BMP-4 can change patterning of developing chick facial primordia. Development 1997; 124:391–398.PubMedGoogle Scholar
  30. 30.
    Barlow AJ, Bogardi JP, Ladher R et al. Expression of chick Barx-1 and its differential regulation by FGF-8 and BMP signaling in the maxillary primordia. Dev Dyn 1999; 214:291–302.PubMedCrossRefGoogle Scholar
  31. 31.
    Abzhanov A, Protas M, Grant BR et al. Bmp4 and morphological variation of beaks in Darwin’s finches. Science 2004; 305:1462–1465.PubMedCrossRefGoogle Scholar
  32. 32.
    Hu D, Helms JA. The role of sonic hedgehog in normal and abnormal craniofacial morphogenesis. Development 1999; 126:4873–4884.PubMedGoogle Scholar
  33. 33.
    Richman JM, Tickle C. Epithelia are interchangeable between facial primordia of chick embryos and morphogenesis is controlled by the mesenchyme. Dev Biol 1989; 136:201–210.PubMedCrossRefGoogle Scholar
  34. 34.
    Gunhaga L, Jessell TM, Edlund T. Sonic hedgehog signaling at gastrula stages specifies ventral telencephalic cells in the chick embryo. Development 2000; 127:3283–3293.PubMedGoogle Scholar
  35. 35.
    Chiang C, Litingtung Y, Lee E et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 1996; 383:407–413.PubMedCrossRefGoogle Scholar
  36. 36.
    Hamburger V, Hamilton HL. A series of normal stages in the development of the chick embryo. Journal of Morphology 1951; 88:49–92.CrossRefGoogle Scholar
  37. 37.
    Jeong J, Mao J, Tenzen T et al. Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev 2004; 18:937–951.PubMedCrossRefGoogle Scholar
  38. 38.
    Hu D, Helms JA. Unpublished data. 2006.Google Scholar
  39. 39.
    Young DL, Schneider RA, Hu D et al. Genetic and teratogenic approaches to craniofacial development. Crit Rev Oral Biol Med 2000; 11:304–317.PubMedGoogle Scholar
  40. 40.
    Machold R, Hayashi S, Rutlin M et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 2003; 39:937–950.PubMedCrossRefGoogle Scholar
  41. 41.
    Kessaris N, Jamen F, Rubin LL et al. Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors. Development 2004; 131:1289–1298.PubMedCrossRefGoogle Scholar
  42. 42.
    Palma V, Ruiz i Altaba A. Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 2004; 131:337–345.PubMedCrossRefGoogle Scholar
  43. 43.
    Belloni E, Muenke M, Roessler E et al. Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet 1996; 14:353–356.PubMedCrossRefGoogle Scholar
  44. 44.
    Nanni L, Ming JE, Bocian M et al. The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet 1999; 8:2479–2488.PubMedCrossRefGoogle Scholar
  45. 45.
    Tamarin A, Crawley A, Lee J et al. Analysis of upper beak defects in chicken embryos following with retinoic acid. J Embryol Exp Morphol 1984; 84:105–123.PubMedGoogle Scholar
  46. 46.
    Abzhanov A, Cordero D. Unpublished data. 2006.Google Scholar
  47. 47.
    Hui CC, Joyner AL. A mouse model of greig cephalopolysyndactyly syndrome: The extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nat Genet 1993; 3:241–246.PubMedCrossRefGoogle Scholar
  48. 48.
    Mo R, Freer AM, Zinyk DL et al. Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development 1997; 124:113–123.PubMedGoogle Scholar
  49. 49.
    Duester G. Families of retinoid dehydrogenases regulating vitamin A function: Production of visual pigment and retinoic acid. Eur J Biochem 2000; 267:4315–4324.PubMedCrossRefGoogle Scholar
  50. 50.
    Li H, Wagner E, McCafFery P et al. A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse. Mech Dev 2000; 95:283–289.PubMedCrossRefGoogle Scholar
  51. 51.
    Mic FA, Molotkov A, Fan X et al. RALDH3, a retinaldehyde dehydrogenase that generates retinoic acid, is expressed in the ventral retina, otic vesicle and olfactory pit during mouse development. Mech Dev 2000; 97:227–230.PubMedCrossRefGoogle Scholar
  52. 52.
    Keeler RF. Teratogenic compounds of Veratrum californicum (Durand) X. Cyclopia in rabbits produced by cyclopamine. Teratology 1970; 3:175–180.PubMedCrossRefGoogle Scholar
  53. 53.
    Keeler RF. Livestock models of human birth defects, reviewed in relation to poisonous plants. J Anim Sci 1988; 66:2414–2427.PubMedGoogle Scholar
  54. 54.
    Incardona JP, Gaffield W, Kapur RP et al. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 1998; 125:3553–3562.PubMedGoogle Scholar
  55. 55.
    Chen JK, Taipale J, Cooper MK et al. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002; 16:2743–2748.PubMedCrossRefGoogle Scholar
  56. 56.
    Peters H, Balling R. Teeth. Where and how to make them. Trends Genet 1999; 15:59–65.PubMedCrossRefGoogle Scholar
  57. 57.
    Tucker AS, Sharpe PT. Molecular genetics of tooth morphogenesis and patterning: The right shape in the right place. J Dent Res 1999; 78:826–834.PubMedGoogle Scholar
  58. 58.
    Jernvall J, Thesleff I. Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev 2000; 92:19–29.PubMedCrossRefGoogle Scholar
  59. 59.
    Cobourne MT, Miletich I, Sharpe PT. Restriction of sonic hedgehog signalling during early tooth development. Development 2004; 131:2875–2885.PubMedCrossRefGoogle Scholar
  60. 60.
    Lee CS, Buttitta L, Fan CM. Evidence that the WNT-inducible growth arrest-specific gene 1 encodes an antagonist of sonic hedgehog signaling in the somite. Proc Natl Acad Sci USA 2001; 98:11347–11352.PubMedCrossRefGoogle Scholar
  61. 61.
    Cobourne MT, Hardcastle Z, Sharpe PT. Sonic hedgehog regulates epithelial proliferation and cell survival in the developing tooth germ. J Dent Res 2001; 80:1974–1979.PubMedCrossRefGoogle Scholar
  62. 62.
    Ferguson MW. Palate development. Development 1988; 103(Suppl):41–60.PubMedGoogle Scholar
  63. 63.
    Rice R, Connor E, Rice DP. Expression patterns of Hedgehog signalling pathway members during mouse palate development. Gene Expr Patterns 2006; 6:206–212.PubMedCrossRefGoogle Scholar
  64. 64.
    Rice R, Spencer-Dene B, Connor EC et al. Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J Clin Invest 2004; 113:1692–1700.PubMedGoogle Scholar
  65. 65.
    Hall JM, Bell ML, Finger TE. Disruption of sonic hedgehog signaling alters growth and patterning of lingual taste papillae. Dev Biol 2003; 255:263–277.PubMedCrossRefGoogle Scholar
  66. 66.
    Farbman Al, Mbiene JP. Early development and innervation of taste bud-bearing papillae on the rat tongue. J Comp Neurol 1991; 304:172–186.PubMedCrossRefGoogle Scholar
  67. 67.
    Hall JM, Hooper JE, Finger TE. Expression of sonic hedgehog, patched, and Gli1 in developing taste papillae of the mouse. J Comp Neurol 1999; 406:143–155.PubMedCrossRefGoogle Scholar
  68. 68.
    Jung HS, Oropeza V, Thesleff I. Shh, Bmp-2, Bmp-4 and Fgf-8 are associated with initiation and patterning of mouse tongue papillae. Mech Dev 1999; 81:179–182.PubMedCrossRefGoogle Scholar
  69. 69.
    Mistretta CM, Liu HX, Gaffield W et al. Cyclopamine and jervine in embryonic rat tongue cultures demonstrate a role for Shh signaling in taste papilla development and patterning: Fungiform papillae double in number and form in novel locations in dorsal lingual epithelium. Dev Biol 2003; 254:1–18.PubMedCrossRefGoogle Scholar
  70. 70.
    Roessler E, Belloni E, Gaudenz K et al. Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. Hum Mol Genet 1997; 6:1847–1853.PubMedCrossRefGoogle Scholar
  71. 71.
    Ming JE, Kaupas ME, Roessler E et al. Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet 2002; 110:297–301.PubMedCrossRefGoogle Scholar
  72. 72.
    Traiffort E, Dubourg C, Faure H et al. Functional characterization of sonic hedgehog mutations associated with holoprosencephaly. J Biol Chem 2004; 279:42889–42897.PubMedCrossRefGoogle Scholar
  73. 73.
    Maity T, Fuse N, Beachy PA. Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. Proc Natl Acad Sci USA 2005; 102:17026–17031.PubMedCrossRefGoogle Scholar
  74. 74.
    Lacombe D, Chateil JF, Fontan D et al. Medulloblastoma in the nevoid basal-cell carcinoma syndrome: Case reports and review of the literature. Genet Couns 1990; 1:273–277.PubMedGoogle Scholar
  75. 75.
    Gorlin RJ. Gorlin (nevoid basal-cell carcinoma) syndrome. In: Gorlin RJ, Cohen MM, Hennekam RCM, eds. Syndromes of the Head and Neck. Oxford: Oxford Univ. Press, 2001.Google Scholar
  76. 76.
    Klein RD, Dykas DJ, Bale AE. Clinical testing for the nevoid basal cell carcinoma syndrome in a DNA diagnostic laboratory. Genet Med 2005; 7:611–619.PubMedCrossRefGoogle Scholar
  77. 77.
    Bale AE. The nevoid basal cell carcinoma syndrome: Genetics and mechanism of carcinogenesis. Cancer Invest 1997; 15:180–186.PubMedCrossRefGoogle Scholar
  78. 78.
    Bale AE, Yu KP. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet 2001; 10:757–762.PubMedCrossRefGoogle Scholar
  79. 79.
    Knudson Jr AG. Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68:820–823.PubMedCrossRefGoogle Scholar
  80. 80.
    Bonifas JM, Bare JW, Kerschmann RL et al. Parental origin of chromosome 9q22.3–q31 lost in basal cell carcinomas from basal cell nevus syndrome patients. Hum Mol Genet 1994; 3:447–448.PubMedCrossRefGoogle Scholar
  81. 81.
    Kalff-Suske M, Wild A, Topp J et al. Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. Hum Mol Genet 1999; 8:1769–1777.PubMedCrossRefGoogle Scholar
  82. 82.
    Kang S, Graham Jr JM, Olney AH et al. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 1997; 15:266–268.PubMedCrossRefGoogle Scholar
  83. 83.
    Hall JG, Pallister PD, Clarren SK et al. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly—A new syndrome? Part I: Clinical, causal, and pathogenetic considerations. Am J Med Genet 1980; 7:47–74.PubMedCrossRefGoogle Scholar
  84. 84.
    Iafolla K, Fratkin JD, Spiegel PK et al. Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome). Am J Med Genet 1989; 33:489–499.PubMedCrossRefGoogle Scholar
  85. 85.
    Shin SH, Kogerman P, Lindstrom E et al. GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Proc Natl Acad Sci USA 1999; 96:2880–2884.PubMedCrossRefGoogle Scholar
  86. 86.
    Honda A, Tint GS, Salen G et al. Defective conversion of 7-dehydrocholesterol to cholesterol in cultured skin fibroblasts from Smith-Lemli-Opitz syndrome homozygotes. J Lipid Res 1995; 36:1595–1601.PubMedGoogle Scholar
  87. 87.
    Shefer S, Salen G, Batta AK et al. Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes. J Clin Invest 1995; 96:1779–1785.PubMedCrossRefGoogle Scholar
  88. 88.
    Roux C, Wolf C, Mulliez N et al. Role of cholesterol in embryonic development. Am J Clin Nutr 2000; 71:1270S–1279S.PubMedGoogle Scholar
  89. 89.
    Stern RS, Rosa F, Baum C. Isotretinoin and pregnancy. J Am Acad Dermatol 1984; 10:851–854.PubMedGoogle Scholar
  90. 90.
    Monga M. Vitamin A and its congeners. Semin Perinatol 1997; 21:135–142.PubMedCrossRefGoogle Scholar
  91. 91.
    Nau H. Teratogenicity of isotretinoin revisited: Species variation and the role of all-trans-retinoic acid. J Am Acad Dermatol 2001; 45:S183–187.PubMedCrossRefGoogle Scholar
  92. 92.
    CDC. Fetal Alcohol Information. 2004, (
  93. 93.
    Jones KL, Smith DW, Ulleland CN et al. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973; 1:1267–1271.PubMedCrossRefGoogle Scholar
  94. 94.
    Sampson PD, Streissguth AP, Bookstein FL et al. Incidence of fetal alcohol syndrome and prevalence of alcohol-related neurodevelopmental disorder. Teratology 1997; 56:317–326.PubMedCrossRefGoogle Scholar
  95. 95.
    Sulik KK. Genesis of alcohol-induced craniofacial dysmorphism. Exp Biol Med (Maywood) 2005; 230:366–375.Google Scholar
  96. 96.
    Ahlgren SC, Thakur V, Bronner-Fraser M. Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure. Proc Natl Acad Sci USA 2002; 99:10476–10481.PubMedCrossRefGoogle Scholar
  97. 97.
    Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 2004; 131:287–298.PubMedCrossRefGoogle Scholar
  98. 98.
    Edison RJ, Muenke M. Central nervous system and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 2004; 350:1579–1582.PubMedCrossRefGoogle Scholar
  99. 99.
    Cordero DR, Tapadia MD, Helms JA. The etiopathologies of holoprosencephaly. Drug Discov Today: Disease Mech 2005; 2:529–537.Google Scholar
  100. 100.
    Cordero DR, Tapadia M, Helms JA. Sonic hedgehog signaling in craniofacial development. In: Ruiz i Altaba A, ed. Hedgehogh-Gli signaling in human disease. Georgetown:; New York: Springer Science+Business Media, 2006:153–176.CrossRefGoogle Scholar
  101. 101.
    Tapadia MD, Cordero D, Helms JA. It’s all in your head: new insights into craniofacial development and deformation. J Anatomy 2005; 207:461–477.Google Scholar

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© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  1. 1.Department of Obstetrics and Gynecology, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  2. 2.Department of Plastic and Reconstructive SurgeryStanford UniversityStanfordUSA

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