Antagonistic effects of Smad2 versus Smad7 are sensitive to their expression level during tooth development

Members of the transforming growth factor-beta (TGF-beta) superfamily regul ate cell proliferation, differentiation, and apoptosis, controlling the dev elopment and maintenance of most tissues. TGF-beta signal is transmitted th rough the phosphorylation of Smad proteins by TGF-beta receptor serine/thre onine kinase. During early tooth development, TGF-beta inhibits proliferati on of enamel organ epithelial cells but the underlying molecular mechanisms are largely unknown. Here we tested the hypothesis that antagonistic effec ts between Smad2 and Smad7 regulate TGF-beta signaling during tooth develop ment. Attenuation of Smad2 gene expression resulted in significant advancem ent of embryonic tooth development with increased proliferation of enamel o rgan epithelial cells, while attenuation of Smad7 resulted in significant i nhibition of embryonic tooth development with increased apoptotic activity within enamel organ epithelium. These findings suggest that different Smads may have differential activities in regulating TGF-beta -mediated cell pro liferation and death. Furthermore, functional haplo-insufficiency of Smad2, but not Smad3, altered TGF-beta -mediated tooth development. The results i ndicate that Smads are critical factors in orchestrating TGF-beta -mediated gene regulation during embryonic tooth development. The effectiveness of T GF-beta signaling is highly sensitive to the level of Smad gene expression.