Mouse Models of Supernumerary Teeth

When using animal models to study changes in tooth number, it is important to keep in mind that tooth number varies dramatically among species, presumably as a functional adaptation in response to environmental pressures [Line, 2003]. Both humans and rodents have reduced mammalian dentition in comparison to the ancestral eutherian formula, in which up to three incisors, one canine, four premolars, and three molars can occur in each dental quadrant. This primitive formula can be seen in some extant mammals, such as certain species of mole. Compared with humans, the adult mouse dentition is severely reduced. Each dental quadrant contains three molars and one incisor, separated by an edentulous region called a diastema (fig. 2), and no pre-molars or canines.

The absence of teeth in the adult mouse diastema does not reflect a lack of tooth development during embryogenesis. Transient epithelial primordia originate in the mouse diastema and reach the bud stage before regressing [Peterkova et al., 2002]. These primordia are presumably evolutionary remnants of the developmental program for tooth formation in species that have teeth between the incisors and molars. Although the di-astema buds initially appear quite robust, they do not progress to the cap stage. In the mandibular antemolar region, two primordia are detected anterior to the presumptive first molar (M1). The more anterior of these structures is thought to regress completely, whilst the more posterior of these, adjacent to M1, may be partially absorbed into the developing M1. The mouse maxilla has not been examined in as much detail as the mandible, but the maxillary diastema is believed to contain as many as seven buds [Peterkova et al., 2000]. The reason for the different number of buds in the maxilla and mandible is not well understood. The elimination of the diastema tooth buds involves apoptosis [Tureckova et al., 1996; Peterkova et al., 2000; Peterkova et al., 2003], but it is not known if cell death is a primary event in failure of the diastema tooth bud to develop, or if it is secondary to failure of the bud to progress to the cap stage.

Supernumerary diastema teeth have been found in a few mutant mouse strains, including mice null for the fibroblast growth factor (FGF) antagonists Spry2 or Spry4 [Klein et al., 2006] (fig. 2), Polaris hypomorphs [Zhang et al., 2003], mice that overexpress ectodysplasin (Eda) or its receptor [Mustonen et al., 2003; Pispa et al., 2004], Pax6 mutants [Kaufman et al., 1995], and mice that are

Fig. 2. Views of the mouse diastema and the presence of diastema teeth in Spry2 null. Side views of the molar and diastema region of wild-type (left) and Spry2-null (right) mice. M1, M2, M3 = 1st, 2nd, and 3rd molars. White arrow points to a diastema tooth.

Fig. 3. Perturbation of signaling pathways can lead to supernumerary teeth by affecting epithelial-mesenchymal interactions. This model summarizes some of the critical signaling interactions between the enamel knot (EK) in the dental epithelium (DE) and the condensing dental mesenchyme (CDM) in a cap-stage molar tooth germ. It is based on data from both gene expression studies and manipulations of tooth germs in vitro [Kettunen et al., 2000; Kratochwil et al., 2002] and from genetic studies on knockout mice [Kassai et al., 2005; Klein et al., 2006]. Arrows indicate a stimulatory effect. The symbol indicates an inhibitory effect of one molecule on the expression of another when solid, and inhibition of signaling by a ligand when dashed. Wnt signal ing induces epithelial FGFs, which in turn induce mesenchymal FGFs via MSX1 and RUNX2. Mesenchymal FGFs induce SHH in the epithelium. FGF signaling to the epithelium and mesenchyme is blocked by SPRY2 and SPRY4, respectively. Loss of function of Spry2 or Spry4 leads to supernumerary tooth development by up-regulating FGF signaling. Wnt signaling may also induce ectodys-plasin (EDA), a molecule that can lead to supernumerary teeth when overexpressed. Ectodin/WISE is a putative inhibitor of both BMP and Wnt signaling, and loss of ectodin/WISE function leads to supernumerary teeth. The precise signaling pathways modulated by ectodin/WISE function have yet to be elucidated.

null for ectodin/WISE, a bone morphogenic protein (BMP) and/or Wnt inhibitor [Kassai et al., 2005]. Interestingly, mutations in the gene encoding Polaris affect sonic hedgehog (SHH) signaling [Murcia et al., 2000; Huangfu et al., 2003; Liu et al., 2005], and mutations in the Eda pathway can be partially rescued by increasing FGF signaling in organ culture [Pispa et al., 1999]. Thus, modulation of pathways that are necessary for molar and incisor development, such as those initiated by SHH, FGFs, and BMPs, can lead to the development of diastema teeth in mice. Pax6 mutants have also been reported to have supernumerary incisors [Quinn et al., 1997].

Another major difference between mouse and human dentition is that mice have only a single set of teeth, whereas in humans the first set of teeth (primary or deciduous teeth) is replaced by a permanent set during childhood. The generation of progressive cycles of teeth appears to be the primitive (ancestral) condition for vertebrates. For example, lower vertebrates like fish replace their teeth throughout life. Most mammals, including humans, have only one cycle of tooth replacement, in which a deciduous (primary) dentition is supplanted by a permanent (secondary) dentition. The secondary dentition develops from lingual buds off of the deciduous lamina. Mice, in contrast, have only one dentition. The mouse therefore provides a simplified model for tooth formation in humans.

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