The importance of signal pathway modulation in all aspects of tooth development.

Most characteristics of tooth shape and pattern can be altered by modulating the signal pathways mediating epithelial-mesenchymal interactions in developing teeth. These regulatory signals function in complex networks, characterized by an abundance of activators or inhibitors. In addition, multiple specific inhibitors of all conserved signal pathways have been identified as modulators in tooth development. The number of teeth as well as molar cusp patterns can be modified by tinkering with several different signal pathways. The inhibition of any of the major conserved signal pathways in knockout mice leads to arrested tooth formation. On the other hand, the stimulation of the Wnt pathway in the oral epithelium in transgenic mice leads to abundant de novo tooth formation. The modulation of some of the signal pathways can rescue the development of vestigial tooth rudiments in the incisor and molar regions resulting in extra premolar-like teeth. The size and the degree of asymmetry of the continuously growing mouse incisor can be modulated by modifying the complex network of FGF, bone morphogenetic protein, and Activin signals, which regulate the proliferation and differentiation of epithelial stem cells. Follistatin, Sprouty, and Sostdc1 are important endogenous inhibitors antagonizing these pathways and they are also involved in regulation of enamel formation, and patterning of teeth in crown and root domains. All these findings support the hypothesis that the diversity of tooth types and dental patterns may have resulted from tinkering with the conserved signal pathways, organized into complex networks, during evolution.