Patterning the dentition: a molecular code for tooth shape

The mouse jaw is demarcated into future incisor and molar-forming regions on a molecular basis before any morphological evidence of tooth development has occurred. Fgf8 is a signalling molecule belonging to the fibroblast growth factor (Fgf) family, which localizes to the future molar regions of the jaw epithelium. In contrast, Bmp4, a signalling molecule of the bone morphogenetic protein (Bmp) family, localizes to the early incisor epithelium. These signalling molecules induce the expression of a number of homeobox-containing genes that encode transcription factor proteins in the tooth-forming neural crest-derived ectomesenchyme of the early jaws.

Initially, signalling from the epithelium to neural crest cells that migrate into the jaws can induce expression of a range of genes. However, expression domains very rapidly become established and then independent of epithelial signalling. It has been suggested that the differing combinations of gene expression patterns act to specify tooth shape (Sharpe, 1995). The ‘odontogenic homeobox code’ predicts that for each tooth-forming region of the early maxilla and mandible, the morphology of the developing tooth is dictated by a specific combination of homeobox genes within the ectomesenchyme (Box 4.2). Thus, for the molar region of mouse jaws, an overlapping code of Barx1 and Dlx2 exists (Fig. 4.3). There are several important points to note with regard to the homeobox model (Sharpe, 2001):

Figure 4.3 Establishing tooth pattern within the jaws.

(A) In the early embryo, neural crest cells migrate into the tooth-forming regions of the primitive maxilla and mandible. (B) Highlight of cell signalling in the mandible. Signalling molecules are produced in the incisor and molar epithelium and these induce differential expression of homeobox genes in the underlying neural crest-derived mesenchyme. Initially, expression of these homeobox genes is dependent upon the presence of signals from the epithelium, but after a short space of time, these patterns of gene expression become independent and fixed. (C) Schematic and simplified representation of the odontogenic homeobox code. Msx1 and Msx2 code for incisors, whilst Dlx2 and Barx1 code for molars.

This final point is important because the peripheral regions of overlap between teeth of different classes appear to be particularly vulnerable with regard to human hypodontia. In these cases, teeth at the end of a series (upper lateral incisors, lower second premolars, third molars) are those most commonly congenitally absent.

Initiation of tooth development

Once the ectomesenchyme within each mouse jaw has been regionalized into presumptive incisor and molar domains, tooth development is initiated within the jaw epithelium. A key player in this process is sonic hedgehog (Shh), a protein produced in localized regions of jaw epithelium where the teeth are going to form. Shh drives proliferation of the dental lamina within these regions, resulting in formation of the tooth buds; if Shh signalling is lost in the early dental lamina, teeth fail to develop. Restriction of Shh production is therefore important in ensuring that teeth develop in the correct regions of the jaws and this is orchestrated by molecular compartmentalization of the jaw epithelium into tooth-forming and non-tooth-forming regions. Specifically, expression of the Shh gene is restricted to the tooth-forming regions because it is repressed throughout the non-dental epithelium by another signalling molecule called Wnt7b. Therefore, tooth formation in the correct regions of the jaws is established via reciprocal expression domains between two different signalling molecules within the jaw epithelium (Fig. 4.4).

Figure 4.4 Expression of Shh and Wnt7b in the early maxilla (upper panel) and mandible (lower panel). Shh signalling is restricted to the early incisor and molar teeth, whilst Wnt7b is expressed in a reciprocal manner, in the regions of the jaw epithelium that will not form teeth.

Once the tooth bud has formed, a number of homeobox-encoding genes subsequently localize to the condensing dental papilla, including Msx1 and Pax9. These genes play an important role in mediating later signalling between the underlying ectomesenchyme and the epithelial bud as tooth development progresses to the cap stage (Fig. 4.5). A loss of either gene leads to the arrest of tooth development at the bud stage in the mouse. Mutations associated with human MSX1 and PAX9 have also been implicated in hypodontia.

Figure 4.5 Expression of Msx1 and Pax9 in the dental mesenchyme surrounding bud stage molar teeth.

Progression to the cap stage: the production of shape

Formation of the tooth bud heralds an important transition for the tooth germ, from bud to cap stage. During the cap stage, the essential shape of the tooth crown is established by folding of the epithelial bud. Folding is mediated by a small group of non-dividing cells within the epithelium of the tooth germ, called the primary enamel knot.

Cells of the enamel knot produce a wealth of signalling molecules and transcription factors, which influence differential growth of the epithelial cap and mediate changes in its shape. The primary enamel knot disappears during the late c/>