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

Abstract

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.

Integration of tooth morphogenesis and innervation by local tissue interactions, signaling networks, and semaphorin 3A

“…These signaling pathways are part of a larger odontogenic signaling network involving genes that are absolutely necessary for tooth formation in man and mouse, such as the MSX1 transcription factor. 23,24,[66][67][68]69,70,71 …”

Maxillary Lateral Incisor Agenesis (MLIA)

“…The evidence of a genetic cause for non-syndromic hypodontia came from the identification of significant family aggregation of MLIA and suggest microdontia of maxillary lateral incisors as part of the same phenotype, segregating as an autosomal dominant trait with incomplete penetrance ; however, modes of transmission linked to X-chromosome and of polygenic or multifactorial type have also been proposed (Chosack et al, 1975). Candidate genes in early steps of tooth development regulation (MSX1, PAX9, AXIN2, TGFa, Activin-b A, LEF1, RUNX2, BMP4, MMP1, MMP20), have been screened for putative mutations in affected families (Kuchler et al, 2010;Lin et al, 2008;Tummers &Thesleff, 2009). …”

Cooperation of nectin‐1 and nectin‐3 is required for normal ameloblast function and crown shape development in mouse teeth

“…Intercellular communication is mediated by several mechanisms, and recent research has focused largely on soluble signaling molecules and their complex networks (Tummers and Thesleff, 2009). Cell-cell adhesion and cell-matrix adhesion are obviously of central importance particularly during morphogenesis and cell differentiation.…”