Recent progresses in signal transduction have revealed that beta-catenin signaling controls embryonic development, tumorogenesis, cell shape, and polarity. The role of this pathway in myocyte shape regulation during cardiac hypertrophy and failure is, however, not clearly defined. Since homozygous knockout of -catenin is embryonically lethal, we have deleted -catenin genes specifically in the heart of adult mice by crossing loxP-flanked -catenin mice with transgenic mice expressing tamoxifen activated Cre protein (MCM) driven by the -myosin heavy chain promoter. Administration of tamoxifen to homozygous loxP-flanked -catenin mice positive for MCM induces the deletion of -catenin only in cardiac myocytes. Immunolabeling with -catenin antibody demonstrates that 90% of cardiac myocytes completely lose their -catenin expression, but maintain normal rod-shape morphology. The intercalated disc of cardiac myocytes lacking -catenin is morphologically unremarkable with normal distribution of vinculin, N-cadherin, desmoplakin, ZO-1, connexin43, -, - and p120 catenins. The expression level of these proteins except -catenin is also similar in tamoxifen treated and control mice with both homozygous loxP-flanked beta-catenin genes and the MCM transgene. Western blot analyses reveal that -catenin increases in the heart of -catenin knockout mice compared to controls. Confocal microscopy also demonstrates that gamma-catenin has significantly increased in the intercalated disc of cardiac myocytes lacking -catenin. Echocardiographic data indicate that the knockout mice maintain normal ventricular geometry and cardiac function. The results suggest that up-regulation of -catenin can compensate for the loss of -catenin in cardiomyocytes to maintain normal cardiac structure and function.