European Archives of Paediatric Dentistry

, Volume 13, Issue 6, pp 297–304 | Cite as

Molecular factors resulting in tooth agenesis and contemporary approaches for regeneration: A review

  • S. M. Cudney
  • A. R. VieiraEmail author


AIM: This review discusses the complex epithelial-mesenchymal interactions that occur during tooth development and systemic anomalies that may result in hypodontia. Emphasis is placed on four interacting signaling families (Shh, FGF, BMP, and Wnt) that have been identified for their integral role in complete tooth development and on several genetic mutations in the MSX1, PAX9, EDA, and AXIN2 genes that arrest tooth development. Proposed treatment options are presented, including signaling factor supplementation and stem cell isolation for bioengineering new teeth.

Key words

Hypodontia tooth agenesis tooth regeneration dental anomalies epithelial-mesenchymal interactions 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Casal M, Lewis JR, Mauldin EA et al. Significant Correction of Disease after Postnatal Administration of Recombinant Ectodysplasin A in Canine X-linked Ectodermal Dysplasia. American J Human Genetics 2007; 81:1050–1056.CrossRefGoogle Scholar
  2. Catón J and Tucker A. Current knowledge of tooth development: patterning and mineralization of the murine dentition. J Anat. 2009; 214:502–515.PubMedCrossRefGoogle Scholar
  3. Chen J, Lan Y, Baek JA, Gao Y, Jiang R. Wnt/beta-catenin signaling plays an essential role in activation of odontogenic mesenchyme during early tooth development. Dev Biol. 2009; 334:174–185.PubMedCrossRefGoogle Scholar
  4. Chishti M, Chishti MS, Muhammad D, Haider M, Ahmad W. A novel missense mutation in MSX1 underlies autosomal recessive oligodontia with associated dental anomalies in Pakastani families. J Hum Genet 2006; 51:872–878.PubMedCrossRefGoogle Scholar
  5. Chuong C, Patel N, Lin J, Jung HS, Widelitz RB. Sonic Hedgehog Signaling Pathway in the Vertebrate Epithelial Appendage Morphogenesis: Perspectives in Development and Evolution. Cell Molecular Life Science 2000; 57:1672–1681.CrossRefGoogle Scholar
  6. Cobourne M, Xavier GM, Depew M et al. Sonic hedgehog signaling inhibits palatogenesis and arrests tooth development in a mouse model of the nevoid basal cell carcinoma syndrome. Dev Biol 2009; 331:38–49.PubMedCrossRefGoogle Scholar
  7. De Coster P, Marks LA, Martens LC, Huysseune Y. Dental agenesis: genetic and clinical perspectives. J Oral Pathol Med. 2009; 38:1–17.PubMedCrossRefGoogle Scholar
  8. Denaxa M, Sharpe PT, Pachnis V. The LIM homeodomain transcription factors Lhx6 and Lhx7 are key regulators of mammalian dentition. Dev Biol. 2009; 333:324–336.PubMedCrossRefGoogle Scholar
  9. Dressler S, Meyer-Marcotty P, Weisschuh N et al. Dental and Craniofacial Anomalies Associated with Axenfeld-Rieger Syndrome with PITX2 Mutation. Case Report Med. 2010; 2010:621984.Google Scholar
  10. Duailibi M, Duailibi SE, Young CS et al. Bioengineered Teeth from Cultured Rat Tooth Bud Cells. J Dent Res 2004; 83:523–528.PubMedCrossRefGoogle Scholar
  11. Fleischmannova J, Matalova E, Tucker AS, Sharpe PT. Mouse models of tooth abnormalities. Eur J Oral Sci 2008; 116:1–10.PubMedCrossRefGoogle Scholar
  12. Gaide O and Schneider P. Permanent Correction of an Inherited Ectodermal Dysplasia with Recombinant EDA. Nature Medicine 2003; 9:614–618.PubMedCrossRefGoogle Scholar
  13. Hu B, Nadiri A, Kuchler-Bopp S et al. Tissue Engineering of Tooth Crown, Root, and Periodontium. Tissue Engineering 2006; 12:2029–2075.Google Scholar
  14. Hudson R, Taniguchi-Sidle A, Boras K, Wiggan O, Hamel PA. Alx-4, a transcriptional activator whose expression is restricted to sites of epithelialmesenchymal interactions. Dev Dvn. 1998; 213:159–169.CrossRefGoogle Scholar
  15. Jarvinem E, Salazar-Ciudad I, Birchmeier W et al. Continuous Tooth Generation in Mouse is Induced by Activated Epithelial Wnt/beta-catenin signaling. Proceedings of the National Academy of Science of the United States of America 2006; 103:18627–18632.CrossRefGoogle Scholar
  16. Jernvall J, Aberg T, Kettunen P, Keränen S, Thesleff I. The Life History of an Embryonic Signaling Center: BMP-4 Induces p21 and is Associated with Apoptosis in the Mouse Tooth Enamel Knot. Development 1998; 125:161–169.PubMedGoogle Scholar
  17. Kangas A, Evans AR, Thesleff I, Jernvall J. Nonindependence of Mammalian Dental Characters. Nature 2004; 432:211–214.PubMedCrossRefGoogle Scholar
  18. Kapadia H, Mues G, D’Souza R. Genes Affecting Tooth Morphogenesis. Orthodontics and Craniofacial Research 2007; 10:105–113.PubMedCrossRefGoogle Scholar
  19. Kavitha B, Priyadharshini V, Sivapathasundharam B, Saraswathi TR. Role of genes in oro-dental diseases. Indian J Dent Res 2010; 21:270–274.PubMedCrossRefGoogle Scholar
  20. Kawashima N. Characterization of dental pulp stem cells: A new horizon for tissue regeneration. Arch Oral Biol 2012; Epub ahead of print.Google Scholar
  21. Kist R, Watson M, Wang X et al. Reduction of Pax9 Gene Dosage in an Allelic Series of Mouse Mutants Causes Hypodontia and Oligodontia. Human Molecular Genetics 2005;14:3605–3617.PubMedCrossRefGoogle Scholar
  22. Kolenc-Fusé F. Tooth Agenesis: in Search of Mutations Behind Failed Dental Development. Med Oral Patol Oral Cir Bucal. 2004; 9:385–395.Google Scholar
  23. Kollar E and Baird G. Tissue Interactions in Embryonic Mouse Tooth Germs. II. The Inductive Role of the Dental Papilla. Journal Embryologic Experimental Morphology 1970; 24:173–186.Google Scholar
  24. Kratochwil K, Galceran J, Tontsch S, Roth W, Grosschedl R. FGF4, a Direct Target of LEF1 and Wnt signaling, can Rescue the Arrest of Tooth Organogenesis in Lef1-/- mice. Genes Dev 2002; 16:3173–3185.PubMedCrossRefGoogle Scholar
  25. Lammi L, Arte S, Somer M et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. American J Human Genetics 2004; 74:1043–1050.CrossRefGoogle Scholar
  26. Liu F, Chu EY, Watt B et al. Wnt/beta-catenin Signaling Directs Multiple Stages of Tooth Morphogenesis. Dev Biol 2008; 313:210–224.PubMedCrossRefGoogle Scholar
  27. Liu F and Millar S. Wnt/ß-catenin Signaling in Oral Tissue Development and Disease. J Dent Res 2010; 89:318–330.PubMedCrossRefGoogle Scholar
  28. Logeart-Avramoglou D, Anagnostou F, Bizios R, Petite H. Engineering Bone: Challenges and Obstacles.J Cell Mol Med 2005; 9:72–84.PubMedCrossRefGoogle Scholar
  29. Mastrogiacomo M, Muraglia A, Komlev V et al. Tissue Engineering of Bone: Search for a Better Scaffold. Orthod Craniofacial Res 2005; 8:277–284.CrossRefGoogle Scholar
  30. Matalova E, Fleischmannova J, Sharpe PT, Tucker AS. Tooth Agenesis: from Molecular Genetics to Molecular Dentistry. J Dent Res 2008; 87:617–624.PubMedCrossRefGoogle Scholar
  31. Mikkola M. Controlling the number of tooth rows. Sci Signal 2009; 2(85):pe53CrossRefGoogle Scholar
  32. Miletich I, Buchner G, Sharpe PT. Barx1 and evolutionary changes in feeding. J Anat. 2005; 207:619–622.PubMedCrossRefGoogle Scholar
  33. Miletich I and Sharpe P. Normal and abnormal dental development. Hum Mol Genet. 2003; 12:69–73.CrossRefGoogle Scholar
  34. Neubüser A, Peters H, Balling R, Martin GR. Antagonist Interactions Between FGF and BMP Signaling Pathways: A Mechanism for Positioning the Sites of Tooth Formation. Cell 1997; 90:247–255.PubMedCrossRefGoogle Scholar
  35. Nie X, Luukko K, Kettunen P. FGF Signalling in Craniofacial Development and Developmental Disorders. Oral Dis 2006a; 12:102–111.PubMedCrossRefGoogle Scholar
  36. Nie X, Luukko K, Kettunen P. BMP Signalling in Craniofacial Development. The Int J of Develop Biol 2006b; 50:511–521.Google Scholar
  37. Nieminen P. Genetic Basis of Tooth Agenesis. J Exp Zool B Mol Dev Evol. 2009; 312B:320–342.CrossRefGoogle Scholar
  38. Ohki K, Kumamoto H, Ichinohasama R et al. PTC gene mutations and expression of SHH, PTC, SMO, and GLi-1 in odontogenic keratocysts. Int J Oral Maxillofac. Surg. 2004; 33:584–592.PubMedCrossRefGoogle Scholar
  39. Pani S. The Genetic Basis of Tooth Agenesis: Basic Concepts and Genes Involved. J Indian Soc Pedod Prev Dent 2011; 29:84–89.PubMedCrossRefGoogle Scholar
  40. Peng L, Ye L, Zhou XD. Mesenchymal stem cells and tooth engineering. Int J Oral Sci. 2009; 1:6–12.PubMedCrossRefGoogle Scholar
  41. Sarkar L and Sharpe P. Inhibition of Wnt signaling by exogenous Mfrzb1 Protein Affects Molar Tooth Size. J Dent Res 2000; 79:920–925.PubMedCrossRefGoogle Scholar
  42. Sloan A and Waddington R. Dental pulp stem cells: what, where, how? Int J Paediatr Dent. 2009; 19:61–70.PubMedCrossRefGoogle Scholar
  43. Song Y, Zhang Z, Yu X et al. Application of lentivirus-mediated RNAi in studying gene function in mammalian tooth development. Dev Dvn. 2006; 235:1334–1344.Google Scholar
  44. Takahashi C, Yoshida H, Komine A et al.Newly Established Cell Lines from Mouse Oral Epithelium Regenerate Teeth when Combined with Dental Mesenchyme. In Vitro Cell Dev. Biol. Anim. 2010; 46:457–468.CrossRefGoogle Scholar
  45. Thesleff I. and Jernvall J. The Enamel Knot: A Putative Signaling Center Regulating Tooth Development. Cold Spring Harb Symp Quant Biol 1997 62:257–267.PubMedCrossRefGoogle Scholar
  46. Thesleff I and Sharpe P. Signalling Networks Regulating Dental Development. Mechanisms of Development 1997; 67:111–123.PubMedCrossRefGoogle Scholar
  47. Thesleff I, Keränen S, Jernvall J. Enamel Knots as Signaling Centers Linking Tooth Morphogenesis and Odontoblast Differentiation. Advances in Den Res 2001; 15:14–18.CrossRefGoogle Scholar
  48. Tojo M, Keränen S, Jernvall J et al. Expression of sonic hedgehog signal transducers, patched and smoothened, in human basal cell carcinoma. Pathol. Int. 1999; 49:687–694.PubMedCrossRefGoogle Scholar
  49. Tucker A, Headon DJ, Schneider P et al. Edar/Eda Interactions Regulate Enamel Knot Formation in Tooth Morphogenesis. Development 2000; 127:4691–4700.PubMedGoogle Scholar
  50. Tucker A and Sharpe P. Molecular genetics of tooth morphogenesis and patterning: the right shape in the right place. J Dent Res. 1999; 78:826–834.PubMedCrossRefGoogle Scholar
  51. Vastardis H, Karimbux N, Guthua SW, Seidman JG, Seidman CE. A Human MSX1 Homeodomain Missense Mutation Causes Evidence Tooth Agenesis. Nature Genetics 1996; 13:417–421.PubMedCrossRefGoogle Scholar
  52. Vieira AR, Meira R, Modesto A, Murray JC. MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. J Dent Res. 2004; 83:723–727.PubMedCrossRefGoogle Scholar
  53. Vieira AR. Unraveling Human Cleft Lip and Palate Research. J Dent Res 2008; 87:119–125.PubMedCrossRefGoogle Scholar
  54. Volponi A, Pang Y, Sharpe PT. Stem cell-based biological tooth repair and regeneration. Trends Cell Biol. 2010; 20:715–722.PubMedCrossRefGoogle Scholar
  55. Wang X and Fan J. Molecular genetics of supernumerary tooth formation. Genesis 2011; 49:261–277.PubMedCrossRefGoogle Scholar
  56. Yamamoto H, Kim EJ, Cho SW, Jung HS. Analysis of Tooth Formation by Reaggregated Dental Mesenchyme from Mouse Embryo. J. Electron. Microsc. (Tokyo) 2003; 52:559–566.CrossRefGoogle Scholar
  57. Yen A and Sharpe P. Stem Cells and Tooth Tissue Engineering. Cell Tissue Res 2008; 331:359–372.PubMedCrossRefGoogle Scholar
  58. Zhao X, Zhang Z, Song Y et al. Transgenically ectopic expression of BMP4 to the MSX1 mutant dental mesenchyme restores downstream gene expression but represses SHH and BMP2 in the enamel knot of wild type tooth germ. Mech Dev. 2000; 99:29–38.PubMedCrossRefGoogle Scholar
  59. Zhang Y, Chen Z, Song YQ, Liu C, Chen YP. Making a tooth: growth factors, transcription factors, and stem cells. Cell Res. 2005; 15:301–316.PubMedCrossRefGoogle Scholar
  60. Zhang Z, Lan Y, Chai Y, Jiang R. Antagonistic actions of Msx1 and Osr2 pattern mammalian teeth into a single row. Science 2009; 323(5918):1232–1234.PubMedCrossRefGoogle Scholar
  61. Zhou J, Gao Y, Zhang Z et al. Osr2 acts downstream of Pax9 and interacts with both Msx1 and Pax9 to pattern the tooth developmental field. Dev Biol. 2011; 353:344–353.PubMedCrossRefGoogle Scholar

Copyright information

© European Academy of Paediatric Dentistry 2012

Authors and Affiliations

  1. 1.Department of Oral BiologyUniversity of Pittsburgh School of Dental MedicinePittsburghUSA

Personalised recommendations