Conditional gene expression in the epidermis of transgenic mice using the tetracycline-regulated transactivators tTA and rTA linked to the keratin 5 promoter

To produce conditional expression of genes in the mouse epidermis we have g enerated transgenic mouse lines in which the tetracycline-regulated transcr iptional transactivators, tTA and rTA, are linked to the bovine keratin 5 p romoter. The transactivator lines were crossed with the tetOlacZ indicator line to test for transactivation in vivo. In the absence of doxycycline, th e K5/tTA line induced beta -galactosidase enzyme activity in the epidermis at a level 500-fold higher than controls, and oral and topical doxycycline caused a dose- and time-dependent suppression of beta -galactosidase mRNA l evels and enzyme activity. In the K5/rTA lines, doxycycline induced beta -g alactosidase activity between 3- and 50-fold higher depending on the founde r line, and this occurred within 24-48 h after dosing. Histochemical analys is of all lines localized beta -galactosidase expression to the basal layer of the epidermis and the outer root sheath of the hair follicle, as well a s other keratin 5 positive tissues. In several K5/rTA lines, skin-specific transactivation was restricted to the hair follicle. Treatment of these dou ble transgenic mice with 12-O-tetradecanoyl-phorbol-13-acetate caused rapid migration of beta -galactosidase marked cells from the hair follicle throu gh the interfollicular epidermis, demonstrating the usefulness of this spec ific double transgenic for fate mapping cells in the epidermis. These resul ts show that the tetracycline regulatory system produces effective conditio nal gene expression in the mouse epidermis, and suggest that it should be a menable to suppression and activation of foreign genes during development a nd specific pathologic conditions relevant to the epidermis.