Development of gene-switch transgenic mice that inducibly express transforming growth factor b1 in the epidermis (inducibleygrowth inhibitionyangiogenesis)

Previous attempts to establish transgenic mouse models to study the functions of transforming growth factor b1 (TGFb1) in the skin revealed controversial roles for TGFb1 in epidermal growth (inhibition vs. stimulation) and resulted in neonatal lethality in one instance. To establish a viable transgenic model for studying functions of TGFb1 in the skin, we have now developed transgenic mice, which allow focal induction of the TGFb1 transgene in the epidermis at different expression levels and at different developmental stages. This system, termed ‘‘gene-switch,’’ consists of two transgenic lines. The mouse loricrin vector targets the GLVPc transactivator (a fusion molecule of the truncated progesterone receptor and the GAL4 DNA binding domain), and a thymidine kinase promoter drives the TGFb1 target gene with GAL4 binding sites upstream of the promoter. These two transgenic lines were mated to generate bigenic mice, and TGFb1 transgene expression was controlled by topical application of an antiprogestin. On epidermal-specific induction of the TGFb1 transgene, the BrdUrd labeling index in the transgenic epidermis decreased 6-fold compared with controls. Induction of the TGFb1 transgene expression also caused epidermal resistance to phorbol 12-myristate 13acetate-induced hyperplasia, with a reduction in both epidermal thickness and BrdUrd labeling compared with those in controls. In addition, TGFb1 transgene expression induced an increase in angiogenesis in the dermis. Given that the TGFb1 transgene can affect both the epidermis and dermis, this transgenic model will provide a useful tool for studying roles of TGFb1 in wound-healing and skin carcinogenesis in the