A Transgenic Mouse Model for Tetracycline Regulated Gene Expression in the Mouse Epidermis
Posted Jun 15 2010 5:00pm
Description of Invention: This technology relates to the creation of several transgenic mouse lines that will produce conditional overexpression of foreign genes in the mouse epidermis. Foreign genes are frequently expressed in mice to create models of human disease by using a promoter or regulatory region that is tissue specific. In previous models expression of the target gene is always on. In these new models expression is conditional such that timing and level of expression can be completely controlled by the investigator. The inventor has taken advantage of the bigenic tetracycline regulatory system first described by Grossen and Bujard to create the present transgenic mouse lines. The system utilizes two transgenic lines that are then bred together to create a double transgenic mouse. One transgenic line expresses the tetracycline regulated transcriptional transactivator tTA or rTA linked to a keratin 5 (K5) promoter. These transgenic lines have been designated K5/tTA and K5/rTA. The K5 promoter is expressed in the epidermis hair follicles and several other squamous epithelia such as tongue trachea and forestomach. The second transgenic line carries the target gene linked to the tetO binding sites for the tTA or rTA proteins. In double transgenic mice, the tTA binds to the tetO sequence and causes high levels of expression of the target gene. However, the ability of the tTA to bind to DNA is prevented by the antibiotic tetracycline. If animals are maintained on tetracycline in the drinking water or feed, the expression of the target gene is suppressed; upon removal of the antibiotic, gene expression is induced. In contrast tetracyclines are required to induce expression of the target gene by the rTA. The ability of this bigenic system to suppress expression of the target gene is crucial for a functional analysis of genes which produce an embryonic or neonatal lethal phenotype when expressed at high levels during gestation. In addition, different levels of gene expression can be achieved through titration of the tetracycline dose. Studies in the inventor's laboratory have confirmed that the K5/tTA and rTA can transactivate expression of target genes in the epidermis at high levels, uniformly throughout the tissue, and that transactivation is tightly controlled by tetracycline analogues. The mouse epidermis is a useful system for modeling for human fibrotic and blistering skin diseases, dissecting the critical factors in wound healing and multistage carcinogenesis in lining epithelia. This conditional expression system should greatly enhance the ability to assess function of specific target genes in these processes, and to create useful in vivo models for the development of novel therapeutics.
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Portfolios: Gene Based Therapies Gene Based Therapies - Research Materials Animal Model
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