Generation of a novel rtTA transgenic mouse to induce time-controlled, tissue-specific alterations in Pax2-expressing cells.

The paired-box transcription factor Pax2 plays a major role in early development of the kidney and the central nervous system. It is expressed in the metanephric mesenchyme of the developing kidney, at the midbrain-hindbrain boundary and the anlagen of the inner ear. The early expression of Pax2, especially in the developing kidney, prompted us to use this locus as a novel genetic tool to introduce temporally-controlled expression of transgenes. We generated a transgenic Pax2-rtTA mouse strain through genetic recombineering using a large BAC clone which drives expression of TetO-controlled transgenes upon doxycycline treatment in natively Pax2-expressing tissues. We show that expression of a TetO-responsive lacZ gene is tightly regulated by addition of doxycycline and can be detected in all Pax2-expressing tissues. Our transgenic Pax2-rtTA mouse thus represents a suitable tool to study the cell fates and molecular pathways in Pax2-positive tissues during development, such as the kidney. We further propose that the Pax2-rtTA tool has great potential to induce time-controlled, tissue-specific alterations for tumorigenic transformation of Pax2-expressing cells for generating in vivo tumor models, such as Wilms tumor.