Overexpression of Smad2 reveals its concerted action with Smad4 in regulating TGF-beta-mediated epidermal homeostasis

Members of the transforming growth factor-beta (TGF-beta) superfamily are c ritical regulators for epithelial growth and can alter the differentiation of keratinocytes. Transduction of TGF-beta signaling depends on the phospho rylation and activation of Smad proteins by heteromeric complexes of ligand -specific type I and II receptors. To understand the function of TGF-beta a nd activin-specific Smad, we generated transgenic mice that overexpress Sma d2 in epidermis under the control of keratin 14 promoter. Overexpression of Smad2 increases endogenous Smad4 and TGF-beta1 expression while heterozygo us loss of Smad2 reduces their expression levels, suggesting a concerted ac tion of Smad2 and -4 in regulating TGF-beta signaling during skin developme nt. These transgenic mice have delayed hair growth, underdeveloped ears, an d shorter tails. In their skin, there is severe thickening of the epidermis with disorganized epidermal architecture, indistinguishable basement membr ane, and dermal fibrosis. These abnormal phenotypes are due to increased pr oliferation of the basal epidermal cells and abnormalities in the program o f keratinocyte differentiation. The ectodermally derived enamel structure i s also abnormal. Collectively, our study presents the first in vivo evidenc e that, by providing an auto-feedback in TGF-beta signaling, Smad2 plays a pivotal role in regulating TGF-beta -mediated epidermal homeostasis. (C) 20 01 Academic Press.