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Vol. 186, No. 1, 2007
Issue release date: July 2007

Unraveling the Molecular Mechanisms That Lead to Supernumerary Teeth in Mice and Men: Current Concepts and Novel Approaches

D’Souza R.N. · Klein O.D.
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Supernumerary teeth are defined as those that are present in excess of the normal complement of human dentition and represent a unique developmental anomaly of patterning and morphogenesis. Despite the wealth of information generated from studies on normal tooth development, the genetic etiology and molecular mechanisms that lead to congenital deviations in tooth number are poorly understood. For developmental biologists, the phenomenon of supernumerary teeth raises interesting questions about the development and fate of the dental lamina. For cell and molecular biologists, the anomaly of supernumerary teeth inspires several questions about the actions and interactions of transcription factors and growth factors that coordinate morphogenesis, cell survival and programmed cell death. For human geneticists, the condition as it presents itself in either syndromic or non-syndromic forms offers an opportunity to discover mutations in known or novel genes. For clinicians faced with treating the dental complications that arise from the presence of supernumerary teeth, knowledge about the basic mechanisms involved is essential. The purpose of this manuscript is to review current knowledge about how supernumerary teeth form, the molecular insights gained through studies on mice that are deficient in certain tooth signaling molecules and the questions that require further research in the field.

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  1. Åberg, T., X.P. Wang, J.H. Kim, T. Yamashiro, M. Bei, R. Rice, H.M. Ryoo, I. Thesleff (2004) Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis. Dev Biol 270: 76–93.
  2. Bei, M., R. Maas (1998) FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development. Development 125: 4325–4333.
  3. Bialek, P., B. Kern, X. Yang, M. Schrock, D. Sosic, N. Hong, H. Wu, K. Yu, D.M. Ornitz, E.N. Olson, M.J. Justice, G. Karsenty (2004) A twist code determines the onset of osteoblast differentiation. Dev Cell 6: 423–435.
  4. Bodin, I., P. Julin, M. Thomsson (1978) Hyperodontia. I. Frequency and distribution of supernumerary teeth among 21,609 patients. Dentomaxillofac Radiol 7: 15–17.
  5. Burzynski, N.J., V.H. Escobar (1983) Classification and genetics of numeric anomalies of dentition. Birth Defects Orig Artic Ser 19: 95–106.
  6. Casci, T., J. Vinos, M. Freeman (1999) Sprouty, an intracellular inhibitor of Ras signaling. Cell 96: 655–665.
  7. de Maximy, A.A., Y. Nakatake, S. Moncada, N. Itoh, J.P. Thiery, S. Bellusci (1999) Cloning and expression pattern of a mouse homologue of drosophila sprouty in the mouse embryo. Mech Dev 81: 213–216.
  8. Dikic, I., S. Giordano (2003) Negative receptor signalling. Curr Opin Cell Biol 15: 128–135.
  9. D’Souza, R.N., T. Åberg, J. Gaikwad, A. Cavender, M. Owen, G. Karsenty, I. Thesleff (1999) Cbfa1 is required for epithelial-mesenchymal interactions regulating tooth development in mice. Development 126: 2911–2920.
  10. D’Souza, R.N., H. Kapadia, A. Vieira (2006) Teeth; in Stevenson, R., J. Hall (eds): Human Malformations and Related Anomalies, ed 2. New York, Oxford University Press, pp 425–465.
  11. Goho, C. (1998) Dental findings in Saethre-Chotzen syndrome (acrocephalosyndactyly type III): report of case. ASDC J Dent Child 65: 136–137.
  12. Guenou, H., K. Kaabeche, S.L. Mee, P.J. Marie (2005) A role for fibroblast growth factor receptor-2 in the altered osteoblast phenotype induced by Twist haploinsufficiency in the Saethre-Chotzen syndrome. Hum Mol Genet 14: 1429–1439.
  13. Guy, G.R., E.S. Wong, P. Yusoff, S. Chandramouli, T.L. Lo, J. Lim, C.W. Fong (2003) Sprouty: how does the branch manager work? J Cell Sci 116: 3061–3068.
  14. Hacohen, N., S. Kramer, D. Sutherland, Y. Hiromi, M.A. Krasnow (1998) sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 92: 253–263.
  15. Huangfu, D., A. Liu, A.S. Rakeman, N.S. Murcia, L. Niswander, K.V. Anderson (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426: 83–87.
  16. Jackman, W.R., B.W. Draper, D.W. Stock (2004) Fgf signaling is required for zebrafish tooth development. Dev Biol 274: 139–157.
  17. Jensen, B.L., S. Kreiborg (1990) Development of the dentition in cleidocranial dysplasia. J Oral Pathol Med 19: 89–93.
  18. Jernvall, J., P. Kettunen, I. Karavanova, L.B. Martin, I. Thesleff (1994) Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf-4 gene. Int J Dev Biol 38: 463–469.
  19. Jernvall, J., I. Thesleff (2000) Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev 92: 19–29.
  20. Kassai, Y., P. Munne, Y. Hotta, E. Penttila, K. Kavanagh, N. Ohbayashi, S. Takada, I. Thesleff, J. Jernvall, N. Itoh (2005) Regulation of mammalian tooth cusp patterning by ectodin. Science 309: 2067–2070.
  21. Kaufman, M.H., H.H. Chang, J.P. Shaw (1995) Craniofacial abnormalities in homozygous Small eye (Sey/Sey) embryos and newborn mice. J Anat 186(Pt 3): 607–617.
  22. Kettunen, P., I. Karavanova, I. Thesleff (1998) Responsiveness of developing dental tissues to fibroblast growth factors: expression of splicing alternatives of FGFR1, -2, -3, and of FGFR4; and stimulation of cell proliferation by FGF-2, -4, -8, and -9. Dev Genet 22: 374–385.
  23. Kettunen, P., I. Thesleff (1998) Expression and function of FGFs-4, -8, and -9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis. Dev Dyn 211: 256–268.
  24. Kettunen, P., J. Laurikkala, P. Itaranta, S. Vainio, N. Itoh, I. Thesleff (2000) Associations of FGF-3 and FGF-10 with signaling networks regulating tooth morphogenesis. Dev Dyn 219: 322–332.
  25. Khaejornbut, J., D.J. Wilson, P.D. Owens (1991) The development and fate of the dental lamina of the mandibular first molar tooth in the rat. J Anat 179: 85–96.
  26. Kim, H.J., D. Bar-Sagi (2004) Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol 5: 441–450.
  27. Klein, O.D., G. Minowada, R. Peterkova, A. Kangas, B.D. Yu, H. Lesot, M. Peterka, J. Jernvall, G.R. Martin (2006) Sprouty genes control tooth number via bidirectional antagonism of epithelial-mesenchymal FGF signaling. Dev Cell 11: 181–190.
  28. Kramer, S., M. Okabe, N. Hacohen, M.A. Krasnow, Y. Hiromi (1999) Sprouty: a common antagonist of FGF and EGF signaling pathways in Drosophila. Development 126: 2515–2525.
  29. Kratochwil, K., J. Galceran, S. Tontsch, W. Roth, R. Grosschedl (2002) FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Genes Dev 16: 3173–3185.
  30. Krause, B., R. Jordan (1965) The Human Dentition before Birth. Philadelphia, Lea & Febiger.
  31. Line, S.R. (2003) Variation of tooth number in mammalian dentition: connecting genetics, development, and evolution. Evol Dev 5: 295–304.
  32. Liu, A., B. Wang, L.A. Niswander (2005) Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 132: 3103–3111.
  33. Lukinmaa, P.L., B.L. Jensen, I. Thesleff, J.O. Andreasen, S. Kreiborg (1995) Histological observations of teeth and peridental tissues in cleidocranial dysplasia imply increased activity of odontogenic epithelium and abnormal bone remodeling. J Craniofac Genet Dev Biol 15: 212–221.
  34. Mandler, M., A. Neubüser (2001) FGF signaling is necessary for the specification of the odontogenic mesenchyme. Dev Biol 240: 548–559.
  35. Minowada, G., L.A. Jarvis, C.L. Chi, A. Neubüser, X. Sun, N. Hacohen, M.A. Krasnow, G.R. Martin (1999) Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed. Development 126: 4465–4475.
  36. Moskow, B.S., A. Bloom (1983) Embryogenesis of the gingival cyst. J Clin Periodontol 10: 119–130.
  37. Mundlos, S., F. Otto, C. Mundlos, J.B. Mulliken, A.S. Aylsworth, S. Albright, D. Lindhout, W.G. Cole, W. Henn, J.H. Knoll, M.J. Owen, R. Mertelsmann, B.U. Zabel, B.R. Olsen (1997) Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89: 773–779.
  38. Murcia, N.S., W.G. Richards, B.K. Yoder, M.L. Mucenski, J.R. Dunlap, R.P. Woychik (2000) The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination. Development 127: 2347–2355.
  39. Mustonen, T., J. Pispa, M.L. Mikkola, M. Pummila, A.T. Kangas, L. Pakkasjarvi, R. Jaatinen, I. Thesleff (2003) Stimulation of ectodermal organ development by Ectodysplasin-A1. Dev Biol 259: 123–136.
  40. Nanci, A. (2003) Ten Cate’s Oral Histology. Development, Structure, and Function, ed 6. St. Louis, Mosby.
  41. Neubüser, A., H. Peters, R. Balling, G.R. Martin (1997) Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell 90: 247–255.
  42. Niswander, L., G.R. Martin (1992) Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. Development 114: 755–768.
  43. Peterkova, R., M. Peterka, H. Lesot (2003) The developing mouse dentition: a new tool for apoptosis study. Ann NY Acad Sci 1010: 453–466.
  44. Peterkova, R., M. Peterka, L. Viriot, H. Lesot (2000) Dentition development and budding morphogenesis. J Craniofac Genet Dev Biol 20: 158–172.
  45. Peterkova, R., M. Peterka, L. Viriot, H. Lesot (2002) Development of the vestigial tooth primordia as part of mouse odontogenesis. Connect Tissue Res 43: 120–128.
  46. Pindborg, J.J. (1970) Pathology of Dental Hard Tissues. Philadelphia, Saunders.
  47. Pispa, J., H.S. Jung, J. Jernvall, P. Kettunen, T. Mustonen, M.J. Tabata, J. Kere, I. Thesleff (1999) Cusp patterning defect in Tabby mouse teeth and its partial rescue by FGF. Dev Biol 216: 521–534.
  48. Pispa, J., T. Mustonen, M.L. Mikkola, A.T. Kangas, P. Koppinen, P.L. Lukinmaa, J. Jernvall, I. Thesleff (2004) Tooth patterning and enamel formation can be manipulated by misexpression of TNF receptor Edar. Dev Dyn 231: 432–440.
  49. Primosch, R.E. (1981) Anterior supernumerary teeth – assessment and surgical intervention in children. Pediatr Dent 3: 204–215.
  50. Quinn, J.C., J.D. West, M.H. Kaufman (1997) Genetic background effects on dental and other craniofacial abnormalities in homozygous small eye (Pax6Sey/Pax6Sey) mice. Anat Embryol (Berl) 196: 311–321.
  51. Reich, A., A. Sapir, B. Shilo (1999) Sprouty is a general inhibitor of receptor tyrosine kinase signaling. Development 126: 4139–4147.
  52. Stellzig, A., E.K. Basdra, G. Komposch (1997) Mesiodentes: incidence, morphology, etiology. J Orofac Orthop 58: 144–153.
  53. Thesleff, I., P. Sharpe (1997) Signalling networks regulating dental development. Mech Dev 67: 111–123.
  54. Trumpp, A., M.J. Depew, J.L. Rubenstein, J.M. Bishop, G.R. Martin (1999) Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch. Genes Dev 13: 3136–3148.
  55. Tucker, A., P. Sharpe (2004) The cutting-edge of mammalian development; how the embryo makes teeth. Nat Rev Genet 5: 499–508.
  56. Tureckova, J., H. Lesot, J.L. Vonesch, M. Peterka, R. Peterkova, J.V. Ruch (1996) Apoptosis is involved in the disappearance of the diastemal dental primordia in mouse embryo. Int J Dev Biol 40: 483–489.
  57. Wang, X.P., T. Åberg, M.J. James, D. Levanon, Y. Groner, I. Thesleff (2005) Runx2 (Cbfa1) inhibits Shh signaling in the lower but not upper molars of mouse embryos and prevents the budding of putative successional teeth. J Dent Res 84: 138–143.
  58. Yusof, W.Z. (1990) Non-syndrome multiple supernumerary teeth: literature review. J Can Dent Assoc 56: 147–149.
  59. Zhang, Q., N.S. Murcia, L.R. Chittenden, W.G. Richards, E.J. Michaud, R.P. Woychik, B.K. Yoder (2003) Loss of the Tg737 protein results in skeletal patterning defects. Dev Dyn 227: 78–90.
  60. Zhang, S., Y. Lin, P. Itaranta, A. Yagi, S. Vainio (2001) Expression of Sprouty genes 1, 2 and 4 during mouse organogenesis. Mech Dev 109: 367–370.
  61. Zhu, J.F., M. Marcushamer, D.L. King, R.J. Henry (1996) Supernumerary and congenitally absent teeth: a literature review. J Clin Pediatr Dent 20: 87–95.

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