Tooth Morphogenesis and Patterning: Molecular Genetics

Abstract

Teeth develop by a series of epithelial–mesenchymal interactions that govern not only where the tooth will form within the developing jaw, but also what type of tooth will develop. Before any sign of tooth development is observed, the patterning information regarding what type of tooth will form has already been determined. Thus an incisor forms in the distal jaw, whereas the molars form more proximally at the back of the jaw. Then, as the tooth develops, a signalling centre, known as the enamel knot, is set up at the centre of the tooth germ, which controls the shape (morphogenesis) of the tooth and the number of cusps which form. The genes involved in these patterning processes are starting to be elucidated and experiments involving knockout mice and misexpression studies have given insights into the molecular genetics of tooth morphogenesis.

Key concepts:

  • How a tooth develops in the embryo?

  • How tooth identity is determined – i.e. to develop as a molar or incisor?

  • How tooth shape is controlled – i.e. number of cusps?

Keywords: tooth; development; shape; identity; enamel knot

Figure 1.

Stages of tooth development. Condensing mesenchyme will form part of the dental papilla.

Figure 2.

Expression of homeobox genes in the developing mandibular process at E10. Frontal view of the head of an E10 embryo showing the mandibular process (dashed line). The expression domains of four homeobox genes are represented as grey blocks within a schematic of the developing mandible. The spots indicate the sites where tooth germs will initiate. Tooth germs develop within Lhx‐expressing mesenchyme. Tooth germs that develop within Barx1 and Dlx domains develop as molars, whereas tooth germs that develop within Msx domains develop as incisors.

Figure 3.

Schematic to show signalling involved in setting up the enamel knot and its action within the tooth germ. (a) Induction of the primary enamel knot (EK) at the bud stage by signals from the mesenchyme. (b) and (c) Stimulation of proliferation outside of the EK and apoptosis within the EK lead to changes in the shape of the tooth germ epithelium and eventual loss of the primary EK by the end of the cap stage. (d) Formation of secondary EKs in molar tooth germs act to control cusp morphogenesis.

close

References

Alappat S, Zhang ZY and Chen YP (2003) Msx homeobox gene family and craniofacial development. Cell Research 13: 429–442.

Chen Y, Bei M, Woo I, Satokata I and Maas R (1996) Msx1 controls inductive signaling in mammalian tooth morphogenesis. Development 122: 3035–3044.

Cobourne MT, Hardcastle Z and Sharpe PT (2001) Sonic hedgehog regulates epithelial proliferation and cell survival in the developing tooth germ. Journal of Dental Research 80: 1974–1979.

Ferguson CA, Tucker AS, Christensen L et al. (1998) Activin is an essential early mesenchymal signal in tooth development that is required for patterning of the murine dentition. Genes & Development 12: 2636–2649.

Ferguson CA, Tucker AS and Sharpe PT (2000) Temporospatial cell interactions regulating mandibular and maxillary arch patterning. Development 127: 403–412.

Gritli‐Linde A, Bei M, Maas R, Zhang XM et al. (2002) Shh signaling within the dental epithelium is necessary for cell proliferation, growth and polarization. Development 129: 5323–5337.

Hardcastle Z, Mo R, Hui CC and Sharpe PT (1998) The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development 125: 2803–2811.

Haworth KE, Wilson JM, Grevellec A et al. (2007) Sonic hedgehog in the pharyngeal endoderm controls arch pattern via regulation of Fgf8 in head ectoderm. Developmental Biology 303: 244–258.

Jernvall J, Aberg T, Kettunen P, Keranen S and Thesleff I (1998) The life history of an embryonic signaling center: BMP‐4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. Development 125: 161–169.

Jernvall J, Keranen SV and Thesleff I (2000) Evolutionary modification of development in mammalian teeth: quantifying gene expression patterns and topography. Proceedings of the National Academy of Sciences of the USA 97: 14444–14448.

Jernvall J, Kettunen P, Karavanova I, Martin LB and Thesleff I (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. International Journal of Developmental Biology 38: 463–469.

Kassai Y, Munne P, Hotta Y et al. (2005) Regulation of mammalian tooth cusp patterning by ectodin. Science 309: 2067–2070.

Klein OD, Minowada G, Peterkova R et al. (2006) Sprouty genes control diastema tooth development via bidirectional antagonism of epithelial‐mesenchymal FGF signaling. Developmental Cell 11: 181–190.

Laurikkala J, Kassai Y, Pakkasjarvi L, Thesleff I and Itoh N (2003) Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot. Developmental Biology 264: 91–105.

Laurikkala J, Mikkola M, Mustonen T et al. (2001) TNF signaling via the ligand‐receptor pair ectodysplasin and edar controls the function of epithelial signaling centers and is regulated by Wnt and activin during tooth organogenesis. Developmental Biology 229: 443–455.

Lu MF, Pressman C, Dyer R, Johnson RL and Martin JF (1999) Function of Rieger syndrome gene in left‐right asymmetry and craniofacial development. Nature 401: 276–278.

Lumsden AG (1988) Spatial organization of the epithelium and the role of neural crest cells in the initiation of the mammalian tooth germ. Development 103(suppl.): 155–169.

Luukko K, Loes S, Furmanek T et al. (2003) Identification of a novel putative signaling center, the tertiary enamel knot in the postnatal mouse molar tooth. Mechanisms of Development 120: 270–276.

Mandler M and Neubuser A (2001) FGF signaling is necessary for the specification of the odontogenic mesenchyme. Developmental Biology 240: 548–559.

Matalova E, Tucker AS and Sharpe PT (2004) Death in the life of a tooth. Journal of Dental Research 83: 11–16.

Mina M and Kollar EJ (1987) The induction of odontogenesis in non‐dental mesenchyme combined with early murine mandibular arch epithelium. Archives of Oral Biology 32: 123–127.

Mitsiadis TA, Angeli I, James C, Lendahl U and Sharpe PT (2003) Role of Islet1 in the patterning of murine dentition. Development 130: 4451–4460.

Mitsiadis TA and Drouin J (2008) Deletion of the Pitx1 genomic locus affects mandibular tooth morphogenesis and expression of the Barx1 and Tbx1 genes. Developmental Biology 313: 887–896.

Neubuser A, Peters H, Balling R and Martin GR (1997) Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell 90: 247–255.

Park BK, Sperber SM, Choudhury A et al. (2004) Intergenic enhancers with distinct activities regulate Dlx gene expression in the mesenchyme of the branchial arches. Developmental Biology 268: 532–545.

Peterkova R, Lesot H, Viriot L and Peterka M (2005) The supernumerary cheek tooth in tabby/EDA mice‐a reminiscence of the premolar in mouse ancestors. Archives of Oral Biology 50: 219–225.

Peters H, Neubuser A, Kratochwil K and Balling R (1998) Pax9‐deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes & Development 12: 2735–2747.

Pispa J, Jung HS, Jernvall J et al. (1999) Cusp patterning defect in Tabby mouse teeth and its partial rescue by FGF. Developmental Biology 216: 521–534.

Ruch JV, Lesot H, Karcher‐Djuricic V and Meyer JM (1984) Extracellular matrix‐mediated interactions during odontogenesis. Progress in Clinical and Biological Research 151: 103–114.

Sarkar L, Cobourne M, Naylor S et al. (2000) Wnt/Shh interactions regulate ectodermal boundary formation during mammalian tooth development. Proceedings of the National Academy of Sciences of the USA 97: 4520–4524.

Satokata I and Maas R (1994) Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genetics 6: 348–356.

Sharpe PT (1995) Homeobox genes and orofacial development. Connective Tissue Research 32: 17–25.

Thomas BL, Tucker AS, Qui M et al. (1997) Role of Dlx‐1 and Dlx‐2 genes in patterning of the murine dentition. Development 124: 4811–4818.

Trumpp A, Depew MJ, Rubenstein JL, Bishop JM and Martin GR (1999) Cre‐mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch. Genes & Development 13: 3136–3148.

Tucker AS, Al Khamis A and Sharpe PT (1998a) Interactions between Bmp‐4 and Msx‐1 act to restrict gene expression to odontogenic mesenchyme. Developmental Dynamics 212: 533–539.

Tucker AS, Headon DJ, Courtney JM, Overbeek P and Sharpe PT (2004) The activation level of the TNF family receptor, Edar, determines cusp number and tooth number during tooth development. Developmental Biology 268: 185–194.

Tucker AS, Headon DJ, Schneider P et al. (2000) Edar/Eda interactions regulate enamel knot formation in tooth morphogenesis. Development 127: 4691–4700.

Tucker AS, Matthews KL and Sharpe PT (1998b) Transformation of tooth type induced by inhibition of BMP signaling. Science 282: 1136–1138.

Tucker AS, Yamada G, Grigoriou M, Pachnis V and Sharpe PT (1999) Fgf‐8 determines rostral‐caudal polarity in the first branchial arch. Development 126: 51–61.

Vaahtokari A, Aberg T, Jernvall J, Keranen S and Thesleff I (1996) The enamel knot as a signaling center in the developing mouse tooth. Mechanisms of Development 54: 39–43.

Vainio S, Karavanova I, Jowett A and Thesleff I (1993) Identification of BMP‐4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development. Cell 75: 45–58.

Zhao X, Zhang Z, Song Y et al. (2000) 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. Mechanisms of Development 99: 29–38.

Further Reading

Chai Y and Maxson RE (2006) Recent advances in craniofacial morphogenesis. Developmental Dynamics 235: 2353–2375.

Fleischmannova J, Matalova E, Tucker AS and Sharpe PT (2008) Mouse models of tooth abnormalities. European Journal of Oral Science 116: 1–10.

http://bite‐it.helsinki.fi/, Gene Expression in Tooth. Gene expression patterns of a wide variety of signalling molecules, transcription factors etc. involved in tooth development from the epithelial thickening stage to the bell stage of development.

Jernvall J and Thesleff I (2000) Reiterative signaling and patterning during mammalian tooth morphogenesis. Mechanisms of Development 92: 19–29.

Kapadia H, Mues G and D'Souza R (2007) Genes affecting tooth morphogenesis. Orthodontics & Craniofacial Research 10: 105–113.

Matalova E, Fleischmannova J, Sharpe PT and Tucker AS (2008) Tooth agenesis: from molecular genetics to molecular dentistry. Journal of Dental Research 87: 617–623.

Tucker AS and Sharpe P (2004) The cutting‐edge of mammalian development; how the embryo makes teeth. Nature Reviews. Genetics 5: 499–508.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Saffron Tucker, Abigail(Mar 2009) Tooth Morphogenesis and Patterning: Molecular Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005989.pub2]