CONDITIONAL TRANSGENE EXPRESSION IN THE HEART

Conditional transgene expression is a potentially useful approach to i nvestigate complex biological systems in vivo. We recently demonstrate d that tetracycline-responsive promoters could be employed to achieve regulated, cardiac-specific expression of target genes in transgenic m ice. To more fully define the quantitative and spatial parameters asso ciated with tetracycline-regulated gene expression in the heart, we cr ossed transgenic mice harboring either a firefly luciferase or a nucle ar-localized bacterial lacZ target gene with strains expressing a tetr acycline-controlled transactivator (tTA) under the regulatory control of 2.9 kb of 5' flanking sequence from the rat alpha-myosin heavy chai n gene. Luciferase activity was induced nearly 300-fold in the hearts of binary-transgenic mice compared with mice carrying only the lucifer ase reporter gene. No significant transactivation was observed in any other tissues examined. Binary transgenics harboring the lacZ reporter gene showed substantial beta-galactosidase activity throughout the he art, but the response of individual cardiac myocytes was heterogeneous . For both reporter genes, tetracycline treatment fully repressed tTA- dependent transactivation. These data provide important insights into the nature of studies that can be successfully addressed using the tet racycline-regulated gene expression system in the heart.