Genes Involved in Tooth Development: Reciprocal Signalling between Epithelium and Mesenchyme

1. Genes Involved in Tooth By fajara

2. Embryonic development of teeth relies on a series of reciprocal inductive signallings between two adjacent tissues, an epithelium and a mesenchyme. Separation and recombination of these two tissues in mice has shown that odontogenesis is induced by the epithelium around embryonic day 10 and two days later the odontogenic potential switches to the mesenchyme (1,2). The mesenchymal cells participating in tooth development form from cranial neural crest (CNC) cells, which delaminate at the junction between the extreme dorsal surface of the neural tube and the ectoderm, and migrate extensively to populate the branchial arches (BA). Any CNC cell population can support tooth development when recombined with oral ectoderm (2). In contrast to the posteriorly located BA and main body axis, the first BA (BA1), from which the mandible and the proximal maxilla develop, does not express Hox genes and tooth development is controlled by local interactions involving non-Hoxhomeobox and other transcriptional regulators

3. Schematic representation of molar tooth development. Genes essential for tooth development are indicated at the developmental stage at which tooth development arrests in mutant mice. They are highlighted in yellow, blue or red, depending on their requirement, respectively, in the epithelium, mesenchyme or enamel knot. Red arrows represent the reciprocal signalling between epithelium and mesenchyme during advancing tooth development. At the bell stage, the two rows of developing ameloblasts and odontoblasts are respectively indicated as bright yellow and dark blue lines at the epitheliomesenchymal surface. Am, ameloblasts, Cm, condensed mesenchyme, Dp, dental papilla; Ek, enamel knot; Ep, epithelium; Mes, mesenchyme, Od, odontoblasts; Sek, secondary enamel knot.

4. GENETIC DEFECTS AFFECTING ALL TEETH

5. Wnt/Lef1 and FGF signalling • The canonical Wnt signals play an essential role during tooth development. Either blocking Wnt co-receptors or knocking-out Lef1, a nuclear mediator of Wnt signalling, lead to an absence of all teeth. Dickkopf1 (Dkk1) is a potent and specific secreted inhibitor of Wnt action, which functions by binding and inhibiting lipoprotein receptor-related protein (LRP) coreceptors required for activation of the canonical Wnt signalling pathway. Transgenic mice expressing Dkk1 in basal epidermal cells (which is likely to diffuse to the adjacent epithelial and mesenchymal cells), exhibit tooth development arrested at the epithelial thickening stage (5). Wnt genes −4, −6, −10a and −10b, which are expressed in the presumptive dental epithelium at this stage, are likely candidates for these Wnt signals involved in the dental lamina to bud stage transition (6,7). Binding of Wnts to their receptors causes formation in the nucleus of active transcription complexes between β-catenin and Lef1, a member of the LEF/TCF family of DNA binding proteins, that activates Wnt target gene expression. Lef1 null mice have tooth development arrested at the bud stage, although the requirement for Lef1 may be earlier when it is expressed in the epithelium (8), suggesting that Wnt signalling is also required for the bud-to-cap transition (9). The fact that tooth development arrests earlier in Dkk1 mice than Lef1 null mice may be due to redundancy of Lef1 with other LEF/TCF family members. At the bud stage, Lef1 is required transiently in the epithelium to generate an inductive signal to the mesenchyme, triggering the formation of the dental papilla (8). Epithelial Fgf4 has been identified as a Lef1 direct target, which in turn induces mesenchymal FGF expression, which is required for Shhepithelial expression in the future enamel knot (10). Epithelial FGF signalling is also required for tooth development as mice deficient for the FGF receptor Fgfr2(IIIb), which is expressed in the epithelium, fail to develop teeth beyond the bud stage (11).

6. The important role that Msx genes play in tooth development is exemplified by mice lacking Msx gene function. Msxldeficient mice exhibit an arrest in tooth development at the bud stage, while Msx2-deficient mice exhibit late defects in tooth development. The co-expression of Msx, Bmp, Lef1, and Activin βA genes and the coincidence of tooth phenotypes in the various knockout mice suggest that these genes reside within a common genetic pathway. Results summarized here indicate that Msx1 is required for the transmission of Bmp4 expression from dental epithelium to mesenchyme and also for Lef1 expression. In addition, we consider the role of other signaling molecules in the epithelial-mesenchymal interactions leading to tooth formation, the role that transcription factors such as Msx play in the propagation of inductive signals, and the role of extracellular matrix. Last, as a unifying mechanism to explain the disparate tooth phenotypes in Msxl- and Msx2-deficient mice, we propose that later steps in tooth morphogenesis molecularly resemble those in early tooth development.

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