Figure 1. Schematic presentation of the morphology of tooth development. (a) Initiation of teeth is seen as thickening of the epithelium in the facial processes and formation of the dental placodes. (b) The budding of the epithelium is accompanied by condensation of the neural crest-derived mesenchymal cells. (c) The enamel knot appears in the epithelium as it undergoes folding morphogenesis and develops into the cap stage. (d) The form of the tooth crown is established during the bell stage, and secondary enamel knots appear in the tips of future cusps. The epithelium buds again to start the development of a secondary tooth. (e) Differentiation of the odontoblasts and ameloblasts and deposition of dentin and enamel start in the cusp tips. (f) After completion of crown formation, dentinogenesis continues in the forming roots and the tooth erupts into the oral cavity. (g) More detailed view of the inset in (e). The differentiation and matrix deposition proceeds as a gradient from the cusp tips to the more cervical region. (h) More detailed view of the inset in (f). Cementum is deposited by cementoblasts differentiating from the dental follicle after the epithelial root sheath disrupts. The periodontal ligament forms and the development of alveolar bone continues. Ab, ameloblasts; Cb, cementoblasts; Ce, cementum; Ds, dental sac; Dt, dentin; Em, enamel; HERS, Hertwig epithelial root sheath; Ob, odontoblasts; Pd, predentin; Pl, periodontal ligament.

Figure 2. Schematic presentation of signalling networks regulating early tooth morphogenesis. The signalling tissues and signalling molecules are indicated in the boxes and transcription factors presumably regulating the signals in the inner boxes. Arrows indicate the signals. Genes that have been shown to be necessary for tooth morphogenesis are indicated below the arrows between stages where the arrest of development occurs in mutant mice. Red colour indicates the signalling centres (dental placode and primary and secondary enamel knots). BMP, bone morphogenetic protein; FGF, fibroblast growth factor; TNF, tumour necrosis factor, Shh, sonic hedgehog.

Figure 3. Visualization of enamel knots, signalling centres in the epithelium. (a) Transverse section of a cap stage mouse tooth (embryonic day 14). Cells of the enamel knot stop proliferating as shown by the lack of bromodeoxyuridine (BrdU) incorporation (red). (b) Three-dimensional view of the enamel knot of the cap stage tooth as visualized by the lack of BrdU incorporation (red) and the expression of Fgf4 (blue). (c) Transverse section of a cap stage mouse tooth (embryonic day 14). Fgf-4 expression, as visualized by in situ hybridization (blue), is limited to the enamel knot. (d) Sagittal section of an embryonic day 16 mouse mandible. Fgf4 expression in the secondary enamel knots (sk) of the first molar (m1) at the bell stage, and in the primary enamel knot (pk) of the second molar (m2) at the cap stage. de, dental epithelium; dm, dental mesenchyme. Bars, 100 m. (Courtesy of Jukka Jernvall and Päivi Kettunen.)