1 Nature Reviews Genetics 2004 Vol: 5(7):499-508. DOI: 10.1038/nrg1380

The cutting-edge of mammalian development; how the embryo makes teeth

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.

Mentions
Figures
Figure 1: Dentition in mice and humans.A comparison of mouse and human dentition. a | Mice have three molars and one incisor in each quadrant that are separated by a toothless diastema. b | The human tooth pattern is much more complex. The layout for deciduous teeth is shown, with six teeth developing in each quadrant: two molars, a premolar, a canine and two incisors. The general shape of the teeth is also distinct between the two species. Figure 2: Stages of tooth development.A schematic frontal view of an embryo head at embryonic day (E)11.5 is shown with a dashed box to indicate the site where the lower (mandibular) molars will form. Below, the stages of tooth development are laid out from the first signs of thickening at E11.5 to eruption of the tooth at around 5 weeks after birth. The tooth germ is formed from the oral epithelium and neural-crest-derived mesenchyme. At the bell stage of development, the ameloblasts and odontoblasts form in adjacent layers at the site of interaction between the epithelium and mesenchyme.These layers produce the enamel and dentin of the fully formed tooth. Figure 3: Pattern of gene expression in the developing tooth.a | Signalling within the epithelium and between the epithelium and the mesenchyme at embryonic day (E)10.5. The diagram shows an isolated mandibular arch. Positive auto-regulatory loops and mutual repression within the epithelium leads to the formation of strict boundaries of gene expression, which set up the presumptive incisor and molar fields. Members of the bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) families of protein in the epithelium induce and inhibit the expression of various homeobox genes. This results in a complex pattern of gene expression in the mesenchyme, across both the proximal–distal and oral–aboral/rostral–caudal axes. b | The odontogenic homeobox code model of dental patterning. The nested expression pattern of homeobox genes in the MANDIBLE produces a homeobox code that defines tooth type. Bapx1, bagpipe homeobox gene 1 homologue; Barx1, BarH-like homeobox 1; Dlx, distal-less homeobox; Gsc, goosecoid; Lhx, LIM homeodomain genes; Msx, homeobox, msh-like; Pitx, paired-related homeobox gene. Figure 4: Tooth type in cases of supernumerary teeth.Overexpressing Eda or its receptor, Edar, causes the formation of supernumerary teeth distal to the first molar24,25. These teeth do not have the classic molar shape of multiple cusps, and are in fact more premolar-like in shape (see tooth shapes in a). Panel a shows a section through a first molar, and Panel b shows a section through a neighbouring supernumerary tooth. Eda, ectodysplasin-A; Edar, Eda receptor. Reproduced with permission from Ref. 25 © (2004) Elsevier Science. Figure 5: Examples of human dental disorders.(a, b) Syndromic oligodontia. a | Severe oligodontia associated with small, conical crowns characteristic of ectodermal dysplasia. b | Panoramic radiograph of subject in (a). c | Non-syndromic hypodontia. Congenital absence of a single mandibular premolar. d | Non-syndromic oligodontia. Absence of multiple teeth but no other recognizable anomalies. Asterisks mark the positions of missing teeth. Images courtesy of M. Cobourne and E. Sheehy, King's College London, UK.
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References
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    • . . . Interestingly, overexpression of the EDA ligand by the same method did not alter cusp number in wild-type mice24 . . .
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    • . . . If Eda is overexpressed early in development, it rescues the tooth-number defect in Eda mutant mice26 . . .
    • . . . Interestingly, the administration to pregnant female mice of a recombinant form of EDA protein that was engineered to cross the placental barrier has recently been shown to rescue the development of many of these ectodermal organs in the offspring, if given from 11 days of gestation26 . . .
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    • . . . It is significant that BMP4 could not rescue incisor development in these experiments, which is consistent with the earlier epithelial role of BMP4 in incisor tooth patterning38. . . .
    • . . . The expression of p21 and Msx2 is induced in the epithelium by mesenchymal BMP4 (Ref. 43), which also has a role in regulating the expression of Shh38, 39 . . .
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    • . . . The importance of BMP4 at this stage is shown by the fact that molar tooth development in Msx1 knockout mice can be rescued, at least to the cap stage, by the addition of BMP4 to the mesenchyme37, 38, 39 . . .
    • . . . The expression of p21 and Msx2 is induced in the epithelium by mesenchymal BMP4 (Ref. 43), which also has a role in regulating the expression of Shh38, 39 . . .
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    • . . . An arrest at the bud stage is also seen in the Runx2 (runt homologue; Cbfa1) mutant, although upper molars make it through to an aberrant cap stage40 . . .
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    • . . . The difference between upper and lower molars can be explained by an upregulation of Runx3, another member of the runt gene family, which occurs only in the MAXILLA42. . . .
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    • . . . Proliferation outside the enamel knot, together with non-proliferation within the enamel knot, coordinates the development of the cervical loops that fold around the condensing mesenchyme44, 45 . . .
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    • . . . Proliferation outside the enamel knot, together with non-proliferation within the enamel knot, coordinates the development of the cervical loops that fold around the condensing mesenchyme44, 45 . . .
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    • . . . In addition, high levels of apoptosis occur within the enamel knot, leading to the eventual loss of the structure and silencing of the signalling centre at the late-cap to early-bell stages (reviewed in Ref. 46) . . .
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    • . . . The ligand Eda is expressed in the dental epithelium far from the enamel knot itself; however, it is cleaved from the membrane and signals through its receptor, Edar, which is expressed in the enamel knot itself47, 48 . . .
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    • . . . The ligand Eda is expressed in the dental epithelium far from the enamel knot itself; however, it is cleaved from the membrane and signals through its receptor, Edar, which is expressed in the enamel knot itself47, 48 . . .
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    • . . . The reported incidence of selective agenesis varies from 1.6% to 9.6%; these values do not include agenesis of third molars, which occurs in approximately 20% of the world population49, 50 . . .
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    • . . . The reported incidence of selective agenesis varies from 1.6% to 9.6%; these values do not include agenesis of third molars, which occurs in approximately 20% of the world population49, 50 . . .
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    • . . . True transformation of incisors to molars, however, is extremely rare51 . . .
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    • . . . In humans, an arginine 31 to proline substitution in the homeodomain of the MSX1 protein was found in one family with autosomal dominant agenesis of the third molar and second premolar52, whereas premature termination of translation at serine 104 was associated with loss of premolars and an orofacial cleft53 . . .
  53. 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) .
    • . . . In humans, an arginine 31 to proline substitution in the homeodomain of the MSX1 protein was found in one family with autosomal dominant agenesis of the third molar and second premolar52, whereas premature termination of translation at serine 104 was associated with loss of premolars and an orofacial cleft53 . . .
  54. Jumlongras, D et al. A nonsense mutation in MSX1 causes Witkop syndrome. Am. J. Hum. Genet. 69, 67-74 , (2001) .
    • . . . A nonsense mutation in the homeobox of MSX1 has also been reported as the cause of Witkop syndrome, which includes tooth agenesis54 . . .
  55. 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) .
    • . . . Two of these involve the formation of a truncated form of the protein at exon 2: one is the result of a frameshift mutation caused by a G insertion at nucleotide 219 (Ref. 55), the other the result of an A to T transversion, which creates a stop codon at lysine 114 (Ref. 56) . . .
  56. Nieminen, P. et al. Identification of a nonsense mutation in the PAX9 gene in molar oligodontia. Eur. J. Hum. Genet. 9, 743-746 , (2001) .
    • . . . Two of these involve the formation of a truncated form of the protein at exon 2: one is the result of a frameshift mutation caused by a G insertion at nucleotide 219 (Ref. 55), the other the result of an A to T transversion, which creates a stop codon at lysine 114 (Ref. 56) . . .
  57. Das, P. et al. Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia. Hum. Genet. 110, 371-376 , (2002) .
    • . . . Recently, in one family, agenesis of all primary and permanent molars was shown to be caused by a heterozygous deletion of the entire PAX9 locus57 . . .
  58. 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) .
    • . . . PITX2 is mutated in Rieger syndrome type 1 (RIEG1)58, an autosomal dominant, haploinsufficient disorder that includes tooth abnormalities as one of its primary features59 . . .
  59. 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) .
    • . . . PITX2 is mutated in Rieger syndrome type 1 (RIEG1)58, an autosomal dominant, haploinsufficient disorder that includes tooth abnormalities as one of its primary features59 . . .
  60. 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) .
    • . . . These tooth defects include dental HYPOPLASIA, anodontia (loss of all teeth) and abnormally shaped teeth60 . . .
  61. Gorlin, R. J., Pindborg, J. & Cohen, M. M. in Syndromes with Unusual Dental Findings 649-651 (McGraw-Hill, New York, 1976) , .
    • . . . Rieger syndrome is one of the most serious causes of tooth agenesis, with an incidence rate of approximately 1: 200,000 (Ref. 61) . . .
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