Key Points
-
Members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families of protein signal from the oral epithelium to the underlying mesenchyme, patterning the presumptive incisor and molar fields in the developing mouth.
-
These signals result in the formation of a nested pattern of homeobox genes that are expressed in the mesenchyme, creating a homeobox code that determines tooth type.
-
Manipulation of this homeobox code causes transformations in tooth type, for example, from incisor to molar.
-
The expression of FGF and BMP proteins in the epithelium is refined by positive-feedback loops and mutual repression.
-
Tooth number can be manipulated by altering the level of ectodysplasin (EDA) signalling.
-
Tooth initiation involves interactions between Sonic hedgehog (SHH) and WNT signalling molecules in the oral epithelium.
-
The shape of the resulting tooth is coordinated by the enamel-knot signalling centre.
-
The cusp number in molar teeth can be manipulated by changing the level of EDA signalling.
-
Human dental disorders have been shown to involve many of the genes that have important roles in early tooth development in the mouse.
Abstract
A wealth of information has recently become available on the molecular signals that are required to form and pattern the dentition in the mouse, shedding light on how important decisions about tooth shape, tooth number and cusp (cone-shaped prominence) number are generated. This information, which has been gleaned principally from knockout mice and manipulation of organ cultures, has been used to identify the genes and developmental processes that underlie the many human disorders in which tooth development is defective. Mouse models of several of these syndromes have also indicated ways in which such conditions could be treated.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Haworth, K. et al. Regionalisation of the early head ectoderm is regulated by endoderm and prepatterns the orofacial epithelium. Development (in the press).
Bei, M. & Maas, R. FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signalling pathways in early tooth development. Development 125, 4325–4333 (1998).
Tucker, A. S., Matthews, K. L. & Sharpe, P. T. Transformation of tooth type induced by inhibition of BMP signalling. Science 282, 1136–1138 (1998). An incisor was transformed into a molar by experimental manipulation of gene expression, providing strong support for the homeobox code theory.
Trumpp, A., Depew, M. J., Rubinstein, J. L. R., Bishop, J. M. & Martin, G. R. Cre-mediated gene inactivation demonstrates that Fgf8 is required for cell survival and patterning of the first branchial arch. Genes Dev. 13, 3136–3148 (1999).
Ferguson, C. A., Tucker, A. S. & Sharpe, P. T. Temporospatial cell interactions regulating mandibular and maxillary arch patterning. Development 127, 403–412 (2000).
Thomas, B. L. et al. Role of Dlx-1 and Dlx-2 genes in patterning of the murine dentition. Development 124, 4811–4818 (1997).
Wilson, J. & Tucker, A. S. Fgf and Bmp signals repress the expression of Bapx1 in the mandibular mesenchyme and control the position of the developing jaw joint. Dev. Biol. 266, 138–150 (2004).
Tucker, A. S., Watson, R. P., Lettice, L. A., Yamada, G. & Hill., B. Bapx1 regulates patterning in the middle ear: altered regulatory role in the transition from the proximal jaw during vertebrate evolution. Development 131, 1235–1245 (2004).
Grigoriou, M., Tucker, A. S., Sharpe, P. T. & Pachnis, V. Expression of Lhx6 and Lhx7, a novel subfamily of LIM homeodomain genes, suggests a role in mammalian head development. Development 125, 2063–2074 (1998).
Tucker, A. S., Yamada, G., Grigoriou, M., Pachnis, V. & Sharpe, P. T. Fgf-8 determines rostral–caudal polarity in the first branchial arch. Development 126, 51–61 (1999).
Rivera-Pérez, J. A., Mallo, M., Gendron-Maguire, M., Gridley, T. & Behringer, R. R. Goosecoid is not an essential component of the mouse gastrula organizer but is required for craniofacial and rib development. Development 121, 3005–3012 (1995).
Yamada, G. et al. Targeted mutation of the murine goosecoid gene results in craniofacial defects and neonatal death. Development 121, 2917–2922 (1995).
Thomas, B. T. & Sharpe, P. T. Patterning of the murine dentition by homeobox genes. Euro. J. Oral Sci. 106, 48–54 (1998).
Stottmann, R. W., Anderson, R. M. & Klingensmith, J. The BMP antagonists chordin and noggin have essential but redundant roles in mouse mandibular outgrowth. Dev. Biol. 240, 457–473 (2001).
Mitsiadis, T. A., Angeli, I., James, C., Lendahl, U. & Sharpe, P. T. Role of Islet1 in the patterning of murine dentition. Development 130, 4451–4460 (2003).
Mucchielli, M. L. et al. Otlx2/RIEG expression in the odontogenic epithelium precedes tooth initiation and requires mesenchyme-derived signals for its maintenance. Dev. Biol. 189, 275–284 (1997).
Lu, M. -F., Pressman, C., Dyer, R., Johnson, R. L. & Martin, J. F. Function of Rieger sundrome gene in left–right asymmetry and craniofacial development. Nature 401, 276–278 (1999).
Liu, W., Selever, J., Lu, M. -F. & Martin, J. F. Genetic dissection of Pitx2 in craniofacial development uncovers new functions in branchial arch morphogenesis, late aspects of tooth morphogenesis and cell migration. Development 130, 6375–6385 (2003).
Lin, C. R. et al. Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 401, 279–282 (1999).
St. Amand, T. R. et al. Antagonistic signals between BMP4 and FGF8 define the expression of Pitx1 and Pitx2 in mouse tooth-forming anlage. Dev. Biol. 217, 323–332 (2000).
Sofaer, J. A. Aspects of the tabby-crinkled-downless syndrome. I The development of Tabby teeth. J. Embryol. Exp. Morph. 22, 181–205 (1969).
Sofaer, J. A. The teeth of the Sleek mouse. Arch. Oral Biol. 22, 299–301 (1977).
Headon, D. J. et al. Gene defect in ectodermal dysplasia implicates a death domain adaper in development. Nature 414, 913–916 (2002)
Mustonen, T. et al. Stimulation of ectodermal organ development by Ectodysplasin-A1. Dev. Biol. 259, 123–136 (2003). Formation of supernumerary teeth by excessive EDA signalling provided the first experimental data on how tooth number is generated.
Tucker, A. S., Headon, D., Courtney, J. -M., Overbeek, P. & Sharpe, P. T. The activation level of the TNF-family receptor, Edar, determines cusp number and tooth number during tooth development. Dev. Biol. 268, 185–194 (2004).
Srivastava, A. K. et al. Ectodysplasin-A1 is sufficient to rescue both hair growth and sweat glands in tabby mice. Hum. Mol. Genet. 10, 2973–2981 (2001).
Gaide, O. & Schneider, P. Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nature Med. 9, 614–618 (2003). The first example of a developmental genetic defect that can be corrected by short-term treatment with a recombinant protein.
Grüneberg, H. The molars of the tabby mouse and a test of the single activated X-chromosome hypothesis. J. Embrol. Exp. Morph. 15, 223–244 (1966).
Sofaer, J. A. Aspects of the tabby-crinkled-downless syndrome. II. Observations on the reaction to changes of genetic background. J. Embryol. Exp. Morph. 22, 207–227 (1969).
Hardcastle, Z., Mo, R., Hui, C. -C. & Sharpe, P. T. The Shh signalling pathway in tooth development:defects in Gli2 and Gli3 mutants. Development 125, 2803–2811 (1998).
Sarkar, L. et al. Wnt/Shh interactions regulate ectodermal boundary formation during mammalian tooth development. Proc. Natl Acad. Sci. USA 97, 4520–4524 (2000).
Neubüser, A., Peters, H., Balling, R. & Martin, G. R. Antagonistic interactions between FGF and BMP signalling pathways: a mechanism for positioning the sites of tooth formation. Cell 90, 247–255 (1997).
Ferguson, C. A. et al. Activin is an essential early mesenchymal signal in tooth development that is required for patterning of the murine dentition. Genes Dev. 12, 2636–2649 (1998).
Peters, H., Neubuser, A., Kratochwil, K. & Balling, R. Pax9- deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev. 12, 2735–2747 (1998).
Chen, Y., Bei, M., Woo, I., Satokata, I. & Maas, R. Msx1 controls inductive signalling in mammalian tooth morphogenesis. Development 122, 3035–3044 (1996). One of the first papers on the interaction between epithelial and mesenchymal genes during tooth development.
Satokata, I. & Maas, R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genet. 6, 348–355 (1994).
Bei, M., Kratochwil, K. & Maas, R. L. Bmp4 rescues a non-cell-autonomous function of Msx1 in tooth development. Development 127, 4711–4718 (2000).
Zhao 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 wildtype tooth germ. Mech. Dev. 99, 29–38 (2000).
Zhang et al. A new function of Bmp4: dual role for Bmp4 in regulation of Sonic hedgehog expression in the mouse tooth germ. Development 127, 1431–1443 (2000).
Aberg, T. et al. Phenotypic changes in dentition of Runx2 homozygote-null mutant mice. J. Histochem. Cytochem. 52, 131–139 (2004).
D'Souza, R. N. et al. Cbfa1 is required for epithelial-mesenchymal interactions regulating tooth development in mice. Development 126, 2911–2920 (1999).
Aberg, T. et al. Runx2 mediates FGF signalling from epithelium to mesenchyme during tooth morphogenesis. Dev. Biol. 207, 76–93 (2004).
Jernvall, J., Aberg, T., Kettunen, P., Keranen, S. & Thesleff, I. The life history of an embryonic signalling center. BMP4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. Development 125, 161–169 (1998).
Jernvall, J., Kettunen, P., Karavanova, I., Martin, L. B. & Thesleff, I. Evidence for the role of the enamel knot as a control centre in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf4 gene. Int. J. Dev. Biol. 38, 463–469 (1994). This paper, together with reference 43, highlights the importance of the enamel knot and its role in cusp formation.
Vaahtokari, A., Åberg, T., Jernvall, J., Keränen, S. & Thesleff, I. The enamel knot as a signalling center in the developing mouse tooth. Mech. Dev. 54, 39–43 (1996).
Tucker, A. S. & Sharpe, P. T. Molecular genetics of tooth morphogenesis and patterning: the right shape in the right place. J. Dental Res. 78, 98–105 (1999).
Elomaa, O. et al. Ectodsyplasin is released by proteolytic shedding and binds to the Edar protein. Hum. Mol. Genet. 10, 953–962 (2001).
Tucker, A. S. et al. Edar/Eda interactions regulate enamel knot formation in tooth morphogenesis. Development 127, 4691–4700 (2000). The first functional evidence that the enamel knot controls tooth-cusp morphogenesis.
Simons, A. L., Stritzel, F. & Stamatiou, J. Anomalies associated with hypodontia of the permanent lateral incisors and second premolar. J. Clin. Pediatr. Dent. 17, 109–111 (1993).
Vastardis, H. The gentics of human tooth agenesis: new discoveries for understanding dental anomalies. Am. J. Orthod. Dentofacial Orthop. 117, 650–656 (2000).
Kantaputra, P. N. & Gorlin, R. J. Clin. Dysmorphol. 1, 128 (1992).
Vastardis, H., Karimbux, N., Guthua, S. W., Seidman, J. G. & Seidman, C. E. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nature Genet. 13, 417–421 (1996). This paper shows a link between the human and mouse dental defects that are caused by mutation of the Msx1 gene (see also reference 36).
Van den Boogaard, M. J., Dorland, M., Beemer, F. A. & van Amstel, H. K. MSX1 mutation is associated with oralfacial clefting and tooth agenesis. Nature Genet. 24, 342–343 (2000).
Jumlongras, D et al. A nonsense mutation in MSX1 causes Witkop syndrome. Am. J. Hum. Genet. 69, 67–74 (2001).
Stockton, D. W., Das, P., Goldenberg, M., D'Souza, R. N. & Patel, P. I. Mutations of PAX9 is associated with oligodontia. Nature Genet. 24, 18–19 (2000).
Nieminen, P. et al. Identification of a nonsense mutation in the PAX9 gene in molar oligodontia. Eur. J. Hum. Genet. 9, 743–746 (2001).
Das, P. et al. Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia. Hum. Genet. 110, 371–376 (2002).
Semina, E. V. et al. Cloning and characterisation of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nature. Genet 14, 392–399 (1996).
Flomen, R. H. et al. Construction and analysis of a sequence-ready map in q25 Rieger syndrome can be caused by haploinsufficiency of RIEG, but also by chromosome break approximately 90kb upstream of this gene. Genomics 47, 409–413 (1998).
Amendt, B. A., Semina, E. V. & Alward, W. L. Rieger syndrome: a clinical, molecular and biochemical analysis. Cell. Mol. Life Sci. 57, 1652–1666 (2000).
Gorlin, R. J., Pindborg, J. & Cohen, M. M. in Syndromes with Unusual Dental Findings 649–651 (McGraw-Hill, New York, 1976).
Gage, P. J., Suh, H. & Camper, S. A. Dosage requirements of Pitx2 for development of multiple organs. Development 126, 4643–4651 (1999).
Alward, W. L. et al. Autosomal dominant iris hypoplasia is caused by a mutation in the Rieger syndrome (RIEG/PITX2) gene. Am. J. Ophthalmol. 125, 98–100.
Ferguson, B. M. et al. Cloning of tabby, the murine homologue of the human EDA gene: evidence for a membrane associated protein with a short collagenous domain. Hum. Mol. Genet. 6, 1589–1594 (1997).
Srivastava, A. K. et al. The tabby phenotype is caused by mutations in a mouse homologue of the EDA gene that reveals novel mouse and human exons and encodes a protein (ectodysplasin-A) with collagenous domains. Proc. Natl Acad. Sci. USA 94, 13069–13074 (1997). First genetic link between tabby mice and the human condition hypohidrotic ectodermal dysplasia.
Headon, D. J. & Overbeek, P. A. Involvement of a novel TNF receptor homolog in hair follicle development. Nature Genet. 22, 370–374 (1999).
Headon, D. J. et al. Gene defect in ectodermal dysplasia implicates a novel death domain adapter in development. Nature 414, 913–916 (2001).
Kere, J. et al. X-linked anhidrotic (hypohydrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nature Genet. 13, 409–416 (1996).
Monreal, A. W., Zonana, J. & Ferguson, B. Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations. Am. J. Hum. Genet. 63, 380–389 (1998).
Monreal, A. W. et al. Mutations in the human homolog of the mouse dl cause autosomal recessive and dominant hypohydrotic ectodermal dysplasia. Nature Genet. 22, 366–369 (1999).
Mundlos, S. et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773–779 (1997).
Matalova, E., Tucker, A. S. & Sharpe, P. T. Death in the life of a tooth. J. Dental Res. 83, 11–16 (2004).
Smith, M. M. & Coates, M. I. in Major Events in Early Vertebrate Evolution. (ed. Ahlberg, P. E.) 223–240 (Taylor and Francis, London, 2001).
Reif, W. -E. Evolution of dermal skeleton and dentotion in vertebrates: the odontode-regulation theory. Evol. Biol. 15, 287–368 (1982).
Smith, M. M. & Johanson, Z. Separate evolutionary origins of teeth from evidence in fossil jawed vertebrates. Science 299, 1235–1236 (2003).
Kratochwil, K., Dull, M., Fariñas, I., Galceran, J. & Grosschedl, R. Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development. Genes Dev. 10, 1382–1394 (1996).
Tucker, A. S., Al Khamis, A. & Sharpe, P. T. Interactions between Bmp-4 and Msx-1 act to restrict gene expression to odontogenic mesenchyme. Dev. Dyn. 212, 533–539 (1998).
MacKenzie, A., Ferguson, M. W. & Sharpe, P. T. Expression patterns of the homeobox gene, Hox-8, in the mouse embryo suggest a role in specifying tooth initiation and shape. Development 115, 403–420 (1992).
Kettunen, P. et al. Associations of FGF-3 and FGF-10 with signaling networks regulating tooth morphogenesis. Dev. Dyn. 219, 322–332 (2000).
Kettunen, P., Karavanova, I. & Thesleff, I. 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 (1998).
Åberg, T., Wozney, J. & Thesleff, I. Expression patterns of bone morphogenetic proteins (bmps) in the developing mouse tooth suggest poles in morphogenesis and cell differentiation. Dev. Dyn. 210, 383–396 (1997).
Sarkar, L. & Sharpe, P. T. Expression of wnt signalling pathway genes during tooth development. Mech. Dev. 85, 197–200 (1999).
Snead, M. L., Luo, W., Lau, E. C. & Slavkin, H. C. Spatial- and temporal-restricted pattern for amelogenin gene expression during mouse molar tooth organogenesis. Development 104, 77–85 (1988).
Bègue-Kirn, C., Krebsbach, P. H., Bartlett, J. D. & Butler, W. T. Dentin sialoprotein, dentin phosphoprotein, enamelysin and ameloblastin: tooth-specific molecules that are distinctively expressed during murine dental differentiation. Euro. J. Oral Sci. 106, 963–970 (1998).
Developmental Biology Programme of the University of Helsinki. Gene Expression in Tooth [online], http://bite-it.helsinki.fi (1996).
Acknowledgements
Work in the authors' laboratories is supported by the Medical Research Council, the Biotechnology and Biological Sciences Research Council and the Wellcome Trust.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Glossary
- ENAMEL
-
The hard outer covering of a tooth, consisting of apatite crystals that contain calcium and phosphate.
- TELEOST FISH
-
A bony fish that belongs to the infraclass Teleostei (comprising more than 20,000 species), which includes nearly all the important food and game fish, and many aquarium fish.
- MESENCHYME
-
Embryonic tissue that is composed of loosely organized, unpolarized cells of both mesodermal and ectodermal (for example, neural crest) origin, with a proteoglycan-rich extracellular matrix.
- DENTIN (OR DENTINE)
-
The dense, yellowish tissue that forms the main part of tooth, between the enamel layer and the pulp cavity.
- PLACODERM
-
An extinct class (Placodermi) of primitive fish, known only from fossil remains, that existed throughout the Devonian period (408–360 million years ago).
- ECTOMESENCHYME
-
Mesenchyme that is derived from cranial neural-crest cells.
- NEURAL CREST
-
A vertebrate-specific migratory cell type that derives from the dorsal-most aspect of the neural tube and contributes to many tissues, including the peripheral nervous system and cranium.
- FATE MAPPING
-
A technique that is used to show how a cell or tissue moves and what it will become during normal development.
- MANDIBLE
-
The lower jaw, derived from the first branchial arch.
- MAXILLA
-
The rostral part of the first branchial arch, which joins with the nasal processes to form the upper jaw.
- HAPLOINSUFFICIENCY
-
When loss of function of one gene copy leads to an abnormal phenotype.
- HYPOPLASIA
-
The underdevelopment of a tissue or organ.
- HYPOHIDROTIC
-
Impairment in the ability to perspire.
Rights and permissions
About this article
Cite this article
Tucker, A., Sharpe, P. The cutting-edge of mammalian development; how the embryo makes teeth. Nat Rev Genet 5, 499–508 (2004). https://doi.org/10.1038/nrg1380
Issue Date:
DOI: https://doi.org/10.1038/nrg1380
This article is cited by
-
Bat teeth illuminate the diversification of mammalian tooth classes
Nature Communications (2023)
-
Tooth number abnormality: from bench to bedside
International Journal of Oral Science (2023)
-
The Notch-mediated circuitry in the evolution and generation of new cell lineages: the tooth model
Cellular and Molecular Life Sciences (2023)
-
FGF4 and FGF9 have synergistic effects on odontoblast differentiation
Medical Molecular Morphology (2023)
-
Prevalence and local causes for retention of primary teeth and the associated delayed permanent tooth eruption
Journal of Orofacial Orthopedics / Fortschritte der Kieferorthopädie (2023)