Transactivation of Hox gene expression in a VP16-dependent binary transgenic mouse system

Mice with aberrant expression of Hox genes have provided valuable insight into the role of Hox class transcription factors in patterning the developing skeleton and the nervous system. However, a recurrent problem is the lethality of mice expressing a Hox-transgene. To circumvent premature death frequently associated with transgenes that interfere with development, we have established a binary transgenic mouse system. Transactivator mice harbor the VP16 gene regulated by a promoter of interest while transresponder mice contain the VP16-responsive immediate early (IE) promoter linked to the gene to be expressed [G.W. Byrne, F.H. Ruddle, Multiplex gene regulation: a two-tiered approach to transgene regulation in transgenic mice, Proc. Natl. Acad. Sci. U.S.A., 86 (1989) 5473-5477]. Here, we report the generation of transresponder mouse strains that harbor murine homeobox genes linked to the IE promoter. We provide evidence that these transgenes are transcriptionally activated in progeny that inherit both a transactivator and transresponder transgene. By microdissection of mouse embryos and reverse transcription polymerase chain reaction (RT-PCR) analysis, we demonstrate that the expression of the Hox-transgenes is restricted to those regions of the mouse embryos where VP16 is present. The ability to activate stable Hox-transgenes in a reproducible fashion now permits a detailed in vivo dissection of the molecular mechanisms that lead to developmental abnormalities caused by deregulated Hox-gene expression.