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Overexpression of Smad7 results in severe pathological alterations in multiple epithelial tissues
Wei He1, Allen G Li, Dongyan Wang
1Department of Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Abstract:
Biochemical studies have shown that Smad7 blocks signal transduction of transforming growth factor beta (TGFbeta); however, its in vivo functions are largely unknown. To determine the functions of Smad7, we have expressed Smad7 in transgenic mice, utilizing a keratin K5 promoter (K5.Smad7). K5.Smad7 mice exhibited pathological changes in multiple tissues and died within 10 days after birth. These mice were born with open eyelids and corneal defects, significantly delayed and aberrant hair follicle morphogenesis, and hyperproliferation in the epidermis and other stratified epithelia. Furthermore, K5.Smad7 mice developed severe thymic atrophy and massive thymocyte death, suggesting that Smad signaling in thymic epithelia is essential for thymocyte survival. Interestingly, in addition to a reduction in Smad phosphorylation, the protein levels of the receptors for TGFbeta, activin and bone morphogenetic protein were significantly decreased in the affected tissues of K5.Smad7 mice. Our study provides evidence that Smad7 is a potent in vivo inhibitor for signal transduction of the TGFbeta superfamily during development and maintenance of homeostasis of multiple epithelial tissues.
Insights
Smad7 inhibits transforming growth factor beta (TGFbeta) signaling in vivo. Transgenic mice expressing Smad7 showed developmental defects and early death, revealing its critical role in epithelial tissue homeostasis.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Signaling
Background:
- Smad7 is known to inhibit transforming growth factor beta (TGFbeta) signaling biochemically.
- The in vivo functions of Smad7, particularly during development, remain largely uncharacterized.
Purpose of the Study:
- To elucidate the in vivo functions of Smad7 during mammalian development.
- To investigate the role of Smad7 in the homeostasis of epithelial tissues.
Main Methods:
- Generation of transgenic mice (K5.Smad7) expressing Smad7 under the control of a keratin K5 promoter.
- Phenotypic analysis of K5.Smad7 mice, including gross pathology, histology, and molecular assessments.
Main Results:
- K5.Smad7 mice exhibited severe developmental abnormalities, including corneal defects, delayed hair follicle morphogenesis, epidermal hyperproliferation, and thymic atrophy.
- These mice experienced significant thymocyte death, indicating Smad signaling is crucial for thymocyte survival.
- Reduced Smad phosphorylation and decreased protein levels of TGFbeta superfamily receptors were observed in affected tissues.
Conclusions:
- Smad7 acts as a potent in vivo inhibitor of TGFbeta superfamily signal transduction.
- Smad7 is essential for the proper development and maintenance of homeostasis in multiple epithelial tissues.