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 critical regulators for epithelial growth and can alter the differentiation of keratinocytes. Transduction of TGF-beta signaling depends on the phosphorylation and activation of Smad proteins by heteromeric complexes of ligand-specific type I and II receptors. To understand the function of TGF-beta and activin-specific Smad, we generated transgenic mice that overexpress Smad2 in epidermis under the control of keratin 14 promoter. Overexpression of Smad2 increases endogenous Smad4 and TGF-beta 1 expression while heterozygous loss of Smad2 reduces their expression levels, suggesting a concerted action of Smad2 and -4 in regulating TGF-beta signaling during skin development. These transgenic mice have delayed hair growth, underdeveloped ears, and shorter tails. In their skin, there is severe thickening of the epidermis with disorganized epidermal architecture, indistinguishable basement membrane, and dermal fibrosis. These abnormal phenotypes are due to increased proliferation of the basal epidermal cells and abnormalities in the program of keratinocyte differentiation. The ectodermally derived enamel structure is also abnormal. Collectively, our study presents the first in vivo evidence that, by providing an auto-feedback in TGF-beta signaling, Smad2 plays a pivotal role in regulating TGF-beta-mediated epidermal homeostasis.
Ito
Y
Y
Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, California 90033, USA.
Sarkar
P
P
Mi
Q
Q
Wu
N
N
Bringas
P
P
Liu
Y
Y
Reddy
S
S
Maxson
R
R
Deng
C
C
Chai
Y
Y
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D003743:Dental Enamel / Q000196:embryology; D004475:Ectoderm / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism*; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053547:Keratin-14; D015603:Keratinocytes / Q000378:metabolism*; D007633:Keratins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D008957:Models, Genetic; D010641:Phenotype; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D013997:Time Factors; D014018:Tissue Distribution; D015534:Trans-Activators / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012313:RNA; D007633:Keratins