Development of gene-switch transgenic mice that inducibly express transforming growth factor beta1 in the epidermis.

Abstract

Previous attempts to establish transgenic mouse models to study the functions of transforming growth factor beta1 (TGFbeta1) in the skin revealed controversial roles for TGFbeta1 in epidermal growth (inhibition vs. stimulation) and resulted in neonatal lethality in one instance. To establish a viable transgenic model for studying functions of TGFbeta1 in the skin, we have now developed transgenic mice, which allow focal induction of the TGFbeta1 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 TGFbeta1 target gene with GAL4 binding sites upstream of the promoter. These two transgenic lines were mated to generate bigenic mice, and TGFbeta1 transgene expression was controlled by topical application of an antiprogestin. On epidermal-specific induction of the TGFbeta1 transgene, the BrdUrd labeling index in the transgenic epidermis decreased 6-fold compared with controls. Induction of the TGFbeta1 transgene expression also caused epidermal resistance to phorbol 12-myristate 13-acetate-induced hyperplasia, with a reduction in both epidermal thickness and BrdUrd labeling compared with those in controls. In addition, TGFbeta1 transgene expression induced an increase in angiogenesis in the dermis. Given that the TGFbeta1 transgene can affect both the epidermis and dermis, this transgenic model will provide a useful tool for studying roles of TGFbeta1 in wound-healing and skin carcinogenesis in the future.

• Authors: X J Wang, K M Liefer, S Tsai, B W O'Malley, D R Roop
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 96 Issue 15 Pg. 8483-8 (Jul 20 1999) ISSN: 0027-8424 [Print] United States
• PMID: 10411901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• Estrenes
• Fungal Proteins
• GAL4 protein, S cerevisiae
• Membrane Proteins
• RNA, Messenger
• Receptors, Progesterone
• Saccharomyces cerevisiae Proteins
• Transcription Factors
• Transforming Growth Factor beta
• loricrin
• lilopristone
• Bromodeoxyuridine
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Bromodeoxyuridine (metabolism)
• DNA-Binding Proteins
• Epidermis (metabolism)
• Estrenes (pharmacology)
• Fungal Proteins (genetics)
• Gene Expression Regulation, Developmental
• Hyperplasia (genetics)
• Membrane Proteins (genetics)
• Mice
• Mice, Transgenic
• Neovascularization, Physiologic (genetics)
• Promoter Regions, Genetic
• RNA, Messenger (metabolism)
• Receptors, Progesterone (genetics)
• Saccharomyces cerevisiae Proteins
• Tetradecanoylphorbol Acetate
• Transcription Factors (genetics)
• Transcriptional Activation
• Transforming Growth Factor beta (biosynthesis, genetics)
• Wound Healing (genetics)