Abstract
Members of the transforming growth factor-beta (TGF-beta) superfamily regulate cell proliferation, differentiation, and apoptosis, controlling the development and maintenance of most tissues. TGF-beta signal is transmitted through the phosphorylation of Smad proteins by TGF-beta receptor serine/threonine kinase. During early tooth development, TGF-beta inhibits proliferation of enamel organ epithelial cells but the underlying molecular mechanisms are largely unknown. Here we tested the hypothesis that antagonistic effects between Smad2 and Smad7 regulate TGF-beta signaling during tooth development. Attenuation of Smad2 gene expression resulted in significant advancement of embryonic tooth development with increased proliferation of enamel organ epithelial cells, while attenuation of Smad7 resulted in significant inhibition 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 proliferation and death. Furthermore, functional haploinsufficiency of Smad2, but not Smad3, altered TGF-beta-mediated tooth development. The results indicate that Smads are critical factors in orchestrating TGF-beta-mediated gene regulation during embryonic tooth development. The effectiveness of TGF-beta signaling is highly sensitive to the level of Smad gene expression.
Highlights
Members of the transforming growth factor- (TGF-) superfamily regulate cell proliferation, differentiation, and apoptosis, controlling the development and maintenance of most tissues
Phosphorylated Smad2 was localized within the nuclei of enamel organ epithelial cells, indicating that activated Smad2 had translocated into the nucleus (Fig. 1E, inset)
We examined the expression pattern of Smad2 and Smad7 during cap and bell stages of tooth development in vivo. Both of these Smads were mainly expressed in inner enamel epithelium and its adjacent dental mesenchyme, indicating that TGF- signaling plays a critical role in regulating continued epithelial-mesenchymal interaction throughout tooth development
Summary
Members of the transforming growth factor- (TGF-) superfamily regulate cell proliferation, differentiation, and apoptosis, controlling the development and maintenance of most tissues. Attenuation of Smad gene expression resulted in significant advancement of embryonic tooth development with increased proliferation of enamel organ epithelial cells, while attenuation of Smad resulted in significant inhibition 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--mediated cell proliferation and death. The results indicate that Smads are critical factors in orchestrating TGF--mediated gene regulation during embryonic tooth development. Smad forms complexes with Smad and Smad after activation by TGF- or activin (9, 14 –16), whereas, it forms complexes with Smad and -5 after activation by BMP [14]
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