Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein

The advent of conditional and tissue-specific recombination systems in gene -targeted or transgenic mice has permitted an assessment of single gene fun ction in a temporally regulated and cell-specific manner. Here we generated transgenic mice expressing a tamoxifen-inducible Cre recombinase protein f used to two mutant estrogen-receptor ligand-binding domains (MerCreMer) und er the control of the ar-myosin heavy chain promoter. These transgenic mice were crossed with the ROSA26 lacZ-flox-targeted mice to examine Cre recomb inase activity and the fidelity of the system. The data demonstrate essenti ally no Cre-mediated recombination in the embryonic, neonatal, or adult hea rt in the absence of inducing agent but > 80% recombination after only four tamoxifen injections. Expression of the MerCreMer fusion protein within th e adult heart did not affect cardiac performance, cellular architecture, or expression of hypertrophic marker genes, demonstrating that the transgene- encoded protein is relatively innocuous. In summary, MerCreMer transgenic m ice represent a tool for temporally regulated inactivation of any loxP-targ eted gene within the developing and adult heart or for specifically directi ng recombination and expression of a loxP-inactivated cardiac transgene: in the heart.