Inhibition of skin development by overexpression of transforming growth factor beta 1 in the epidermis of transgenic mice.

Abstract

To assess the effect of transforming growth factor (,3 on the skin in vivo, we have targeted its expression to the epidermis of transgenic mice. To ensure that active TGF-P1 was expressed, we used a porcine TGF-fji cDNA with mutations of Cys-223 --Ser and Cys-225 --Ser, which allow constitutive activation. Mice expressing the mutant transforming growth factor ,13 transgene exhibited a marked phenotype at birth. The skin was very shiny and tautly stretched. These animals were rigid and appeared to be restricted in their ability to move and breathe; death occurred within 24 hr. Histologically, the most prominent features of the skin were a compact orthohyperkeratosis and a reduction in the number of hair follicles. Pulse-labeling studies with 5-bromodeoxyuridine demonstrated a marked reduction in the number of replicating cells in the epidermis and hair follicles. Thus, the macro-and microscopic appearance of these mice, as well as their neonatal lethality, most likely result from inhibition of normal skin development and suppression of epithelial cell proliferation by the overexpression of transforming growth factor Pi.

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

“…TGF-␤1 is a potent modulator of cell growth, exerting stimulatory or inhibitory effects on cell proliferation on various cell types. In transgenic mice overexpressing TGF-␤1 in the epidermis and mammary gland, cell proliferation was inhibited, consistent with the abnormal development of the skin and the mammary epithelium respectively (Pierce et al, 1993;Sellheyer et al, 1993). Inhibition of cell proliferation by TGF-␤1 was also observed in early lung bud cultured in vitro (Serra et al, 1994).…”

“…The expression of TGF-␤1 in mammary gland driven by the mouse mammary tumor virus (MMTV) promoter inhibited mammary ductal growth and branching morphogenesis in transgenic mice (Pierce et al, 1993). Similarly, the targeted expression of TGF-␤1 in epidermis inhibited the skin development in transgenic mice (Sellheyer et al, 1993). In vitro, TGF-␤1 inhibited branching morphogenesis in cultured lung explants (Serra et al, 1994).…”

“…Cytokines released by the infiltrating cells following TGF-␤1 treatment may be directly involved in the subsequent angiogenic responses. In transgenic mice that overexpressed TGF-␤1 in mammary gland (Pierce et al, 1993), liver (Sanderson et al, 1995), central nervous system (Wyss-Coray et al, 1995) and epidermis (Sellheyer et al, 1993), no inflammation or angiogenesis was observed. In the present study, TGF-␤1 expressed in the respiratory epithelium inhibited the pulmonary vascular development without causing inflammation.…”

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

“…By contrast, mice with a targeted deletion of the TGF-b1 gene showed hyperproliferation in the epidermis . In addition, TGF-b1 overexpression in the epidermis of transgenic mice may cause either an increase or a decrease of proliferation possibly depending on the pattern of transgene expression (Sellheyer et al, 1993;Cui et al, 1995). Some explanation for these seemingly contradictory results can be provided by the notion that inhibition and promotion of proliferation through the three di erent TGF-b isoforms, TGF-b1, -b2, -b3, is balanced and that there may be a cross regulation between isoforms (Escherick et al, 1993).…”

“…Therefore, TGF-b has also been implicated in epithelial carcinogenesis due to its various e ects on epithelial cells. TGF-b is a potent negative growth regulator of epithelial cells and can alter their cellular phenotypes (Co ey et al, 1988;Mansbridge and Hanawalt, 1988;Choi and Fuchs, 1990;Sellheyer et al, 1993). Besides its expression in basal cells of normal epidermis TGF-b is induced in the suprabasal compartment of the epidermis in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, TPA (Akhurst et al, 1988;Pelton et al, 1991).…”