Signaling networks regulating tooth organogenesis and regeneration, and the specification of dental mesenchymal and epithelial cell lineages

Abstract

Teeth develop as ectodermal appendages from epithelial and mesenchymal tissues. Tooth organogenesis is regulated by an intricate network of cell-cell signaling during all steps of development. The dental hard tissues, dentin, enamel, and cementum, are formed by unique cell types whose differentiation is intimately linked with morphogenesis. During evolution the capacity for tooth replacement has been reduced in mammals, whereas teeth have acquired more complex shapes. Mammalian teeth contain stem cells but they may not provide a source for bioengineering of human teeth. Therefore it is likely that nondental cells will have to be reprogrammed for the purpose of clinical tooth regeneration. Obviously this will require understanding of the mechanisms of normal development. The signaling networks mediating the epithelial-mesenchymal interactions during morphogenesis are well characterized but the molecular signatures of the odontogenic tissues remain to be uncovered.

Figure 1.

The dental formula of human and mouse, and a schematic representation of tooth development. The permanent dentition of human consists of two incisors, a canine, two premolars, and three molars in each half of the jaw (A). Mice have one incisor and three molars separated by a toothless diastema in each half of the jaw (B). Tooth development starts from the dental lamina, a thickening of the epithelium. Individual placodes form within the dental lamina. The growing epithelium forms a bud and the dental mesenchyme condenses around the epithelium. During morphogenesis, the epithelial tissue folds to cap and bell shapes. Primary and secondary enamel knots in the enamel organ regulate the growth and shape of the tooth. During cell differentiation, enamel-secreting ameloblasts and dentin-secreting odontoblasts mature from the epithelial and mesenchymal cell compartments. The permanent tooth develops lingually to the deciduous tooth from an extension of the dental lamina (C).

Figure 2.

Cross talk between epithelium and mesenchyme through the conserved signaling pathways regulates all aspects of tooth development. When tooth development is initiated, signals from the epithelium activate a set of transcription factors in the mesenchyme, leading to condensation of the mesenchyme and formation of the epithelial placode (A). The enamel knot is a signaling center expressing multiple signaling molecules that induce reciprocal signals from the mesenchyme. Enamel knots determine the position of the cusps and initiate differentiation of odontoblasts (B). Tgfβ, Bmp, and Shh signaling regulate epithelial-mesenchymal interactions in the cervical loop of the mouse incisor. They support the maintenance and proliferation of the stem cells as well as ameloblast differentiation and enamel production (C).

Figure 3.

Shift of the odontogenic potential from epithelium to mesenchyme between dental lamina and placode stages as shown by reciprocal tissue recombinations (Mina and Kollar 1987). Epithelium is capable of inducing tooth development when recombined with nondental mesenchyme until E11 stage of mouse development. At E12 the odontogenic potential has shifted to mesenchyme, and it can induce tooth development when recombined with nondental epithelium (A). Pitx2 is expressed in the dental lamina of the mouse lower jaw at E11 (t = tongue) (B). At E12.5 the Pitx2 expression is restricted to the placode epithelium of the incisors (arrows) and molars (asterisks) (C).

Figure 4.

Bmp4 is one of the signals regulating ameloblast induction. A schematic view of the postnatal mouse incisor shows the asymmetrical deposition of enamel only on the labial side of the tooth and the cervical loop stem cell niche (A). Amelogenin protein is present in the ameloblasts (a) and in the first enamel matrix on the labial side of newborn (NB) incisor (arrow) but not on the lingual side [asterisk; o, odontoblasts]) (B). Bmp4 is expressed in the mesenchyme and is intense in the odontoblasts (arrows) of the developing incisor at E16. The white line surrounds the epithelium (C). A bead soaked in Bmp4 protein induces ameloblastin expression in E16 incisors (D). (B and D reprinted, with permission, from Wang et al. 2004.)

Figure 5.

Supernumerary teeth, tooth replacement, and continuous tooth renewal. Overexpression of ectodysplasin in the surface epithelium results in development of a supernumerary tooth (arrow) in front of the molars (m1-3) in the K14-Eda mice (A). The rudiment of the supernumerary tooth (blue arrow) in front of the first molar (red arrow) can be visualized by Shh expression in E14.5 lower jaw of K14-Eda embryo (B). The permanent canine (C) of the ferret develops as an extension of the dental lamina (dl) on the lingual side of the deciduous canine (dC) at E33 (C). Both deciduous and permanent canine express Pitx2 in the epithelium (D). Sostdc1 is expressed in the intersection between the dental lamina and the deciduous third premolar (dP3) at the time when permanent P3 is initiated in the E35 ferret embryo (arrow) (E). Stimulation of Wnt signaling by stabilized β-catenin in mouse oral epithelium leads to the development of multiple small teeth from a single E14 mutant tooth germ cultured under the kidney capsule (F). Fgf20 is expressed in the enamel knots of upper and lower molars of E14.5 wild-type mouse embryos (G). Multiple enamel knots expressing Fgf20 have been induced in the dental epithelium of β-cat^Δex3K14/+ embryos (H).