Development of gene-switch transgenic mice that inducibly express transforming growth factor beta 1 in the epidermis

Previous attempts to establish transgenic mouse models to study the functio ns of transforming growth factor beta 1 (TGF beta 1) in the skin revealed c ontroversial roles for TGF beta 1 in epidermal growth (inhibition vs. stimu lation) and resulted in neonatal lethality in one instance, To establish a viable transgenic model for studying functions of TGF beta 1 in the skin, w e have now developed transgenic mice, which allow focal induction of the TG F beta 1 transgene in the epidermis at different expression levels and at d ifferent developmental stages. This system, termed "gene-switch," consists of two transgenic lines. The mouse loricrin vector targets the GLVPc transa ctivator (a fusion molecule of the truncated progesterone receptor and the GAL4 DNA binding domain), and a thymidine kinase promoter drives the TGF be ta 1 target gene with GAL4 binding sites upstream of the promoter. These tw o transgenic lines were mated to generate bigenic mice, and TGF beta 1 tran sgene expression was controlled by topical application of an antiprogestin, On epidermal-specific induction of the TGF beta 1 transgene, the BrdUrd la beling index in the transgenic epidermis decreased 6-fold compared with con trols. Induction of the TGF beta 1 transgene expression also caused epiderm al resistance to phorbol 12-myristate 13-acetate induced hyperplasia, with a reduction in both epidermal thickness and BrdUrd labeling compared with t hose in controls. In addition, TGF beta 1 transgene expression induced an i ncrease in angiogenesis in the dermis, Given that the TGF beta 1 transgene can affect both the epidermis and dermis, this transgenic model will provid e a useful tool for studying roles of TGF beta 1 in wound-healing and skin carcinogenesis in the future.