Smad7 Inhibits Wnt Signaling

Abstract

In an effort to better understand skin development, Han et al. created transgenic mice in which the expression of the inhibitory Smad, Smad7, can be induced in keratinocytes and epidermal stem cells. Smad7 was chosen because its expression is increased in pathological skin conditions. An inducible system was required to allow more precise control of the concentration of Smad7 and because constitutive expression of Smad 7 in keratinocytes of transgenic mice is embryonic lethal. Expression of Smad7 during embryogenesis disrupted hair follicle morphogenesis and differentiation. Expression in adults also inhibited hair follicle growth, promoted sebaceous gland growth, and caused epidermal hyperplasia. At concentrations that produced the effects noted, Smad7 (in the inducible system or in a low expressing constitutive transgenic mouse) did not inhibit transforming growth factor-β (TGF-β) signaling (detected as phosphorylated Smad2) or bone morphogenetic protein (BMP) signaling (detected as phosphorylated Smad 1, 5, and 8) and did not inhibit the expression of some Smad target genes. Thus, Smad7 at the concentrations that caused phenotypic changes was not completely effective in blocking Smad signaling. Wnt and hedgehog signaling are also involved in hair follicle and sebaceous gland development. In skin, increased expression of Smad7 caused a decrease in the abundance of β-catenin, a key component of the Wnt signaling pathway, without altering β-catenin transcription. In Smad7 mice crossed with mice expressing a Wnt reporter gene, less reporter gene expression was visible in the mice in which Smad7 expression was increased. Both acute and prolonged expression of Smad7 decreased the abundance of β-catenin. The authors used cultured cells to show that Smad7 promoted the proteasomal-mediated degradation of β-catenin. Cotransfection experiments suggested that Smad7 recruited the E3 ubiquitin ligase Smurf to β-catenin to mediate ubiquitination of β-catenin. A comparison of aged wild-type skin and skin from 7-month-old Smad7-overexpressing mice showed similar phenotypic skin changes and similar expression levels of the Smad7 transcript. Skin from aged mice also showed a reduction in β-catenin abundance compared with skin from wild-type young mice. All of these results suggest that in skin, at physiological concentrations, Smad7 is a regulator of Wnt signaling rather than TGF-β signaling (see Millar for discussion). G. Han, A. G. Li, Y.-Y. Liang, P. Owens, W. He, S. Lu, Y. Yoshimatsu, D. Wang, P. Ten Dijke, X. Lin, X.-J. Wang, Smad7-induced β-catenin degradation alters epidermal appendage development. Dev. Cell 11 , 301-312 (2006). [PubMed] S. E. Millar, Smad7: Licensed to kill β-catenin. Dev. Cell 11 , 274-276 (2006). [PubMed]