002   The Molecular Basis of Tooth Development and Its Implications in Signaling Systems in Hair Development

Ichiro Satokata Div. of Developmental Biology, Dept. of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Epithelial-mesenchymal interactions govern the initiation of organ development, subsequent morphogenesis and terminal cytodifferentiation. The developing tooth of the mouse is a good model for studying the molecular basis of the signaling systems in epithelial-mesenchymal interactions. Recently, a number of genes which encode growth factors, transcription factors and cell surface molecules have been identified that play a role for tooth development and parts of the molecular details of signaling systems have been elucidated, particularly in the signal families BMP, FGF, Shh and Wnt. Antagonistic signaling of FGF8 and BMP2, -4 is suggested to determine the sites of dentition by restricting the expression sites of a paired box gene Pax9. Shh and a homeobox gene Pitx2 are also candidates for determinants of dentition sites. Subsequently, the four epithelial signal families induce differential activation of key transcription factors, resulting in determination of tooth identity and morphogenesis. FGF8 induces homeobox genes Barx1, Lhx6, -7, Msx1, Dlx1, -2, and a member of TGF-b superfamily ActivinbA. FGF4 induces Msx1. BMP2, -4 induce Msx1, -2, Dlx2, a HMG-box gene Lef1 and inhibit Barx1.Wnts also induce Lef1. Shh induces zinc-finger genes Gli1, -2, -3. By the analyses of gene knockout mice, several of these genes have been shown to perform essential functions in determination of tooth identity and morphogenesis. The mesenchymal expression of Msx1 which is induced by the epithelial signals of BMP2, -4 at the lamina stage induces mesenchymal expression of Bmp4 at the bud stage, resulting in formation of a positive feedback loop in the mesenchyme. The mesenchymal BMP4 signaling in turn induces the expression of Msx2, Lef1 and a cyclin-dependent kinase inhibitor p21 in the enamel knot of the epithelium. BMP2, -4, Msx2 and p21 in the enamel knot inhibit epithelial cell proliferation and induce apoptosis, whereas FGF4, -9 in the enamel knot stimulate cell proliferation of both epithelium and mesenchyme. Such an antagonistic signaling of BMP and FGF in the enamel knot is thought to regulate the balance between cell proliferation and apoptosis during tooth morphogenesis. Synergistic and antagonistic effects of signaling molecules and transcription factors are reciprocally and recursively used between epithelium and mesenchyme during tooth development. As the several studies have shown that genes which regulate tooth development are also required for development of other ectodermal organs such as hair follicle and mammary gland, a better understanding of the molecular basis of tooth development may provide an important clue to elucidate the signaling systems in hair development.