DOXYCYCLINE-MEDIATED QUANTITATIVE AND TISSUE-SPECIFIC CONTROL OF GENE-EXPRESSION IN TRANSGENIC MICE

The tet regulatory system in which doxycycline (dox) acts as an induce r of specifically engineered RNA polymerase II promoters was transferr ed into transgenic mice. Tight control and a broad range of regulation spanning up to five orders of magnitude were monitored dependent on t he dox concentration in the water supply of the animals, Administratio n of dox rapidly induces the synthesis of the indicator enzyme lucifer ase whose activity rises over several orders of magnitude within the f irst 4 h in some organs, Induction is complete after 24 h in most orga ns analyzed. A comparable regulatory potential was revealed with the t et regulatory system where dox prevents transcription activation, Dire cting the synthesis of the tetracycline-controlled transactivator (tTA ) to the liver led to highly specific regulation in hepatocytes where, in presence of dox, less than one molecule of luciferase was detected per cell, By contrast, a more than 10(5)-fold activation of the lucif erase gene was observed in the absence of the antibiotic. This regulat ion was homogeneous throughout but stringently restricted to hepatocyt es, These results demonstrate that both tetracycline-controlled transc riptional activation systems provide genetic switches that permit the quantitative control of gene activities in transgenic mice in a tissue -specific manner and, thus, suggest possibilities for the generation o f a novel type of conditional mutants.