ギャップ結合蛋白遺伝子変異マウスの分子解剖学的研究

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We created mice harboring an nls-lacZ gene in place of connexin45, which encodes the only known gap junction protein in the primitive heart before embryonic dey 9, using the cre-loxPsystem. Heterologous recombinant mice revealed Lac Z signals in the nucleus in various tissues : some nuclei in the brain, retina, intestinal and vascular smooth muscles, endothelial cells of blood vessels and endocardium, and impulse conducting fibers of the heart. Connexin45-deficient mice died of heart failure at around embryonic day 10. They initiated heart contractions, but conduction block appeared ithin 24 hours after the first contractions. Their cardiac walls displayed an endocardial cushion defect, while the cardiac jelly was present. These abnormalities were caused by impairment of the epithelial-mesenchymal transformation of the cardiac endothelium. Activation of the endothelium depended on the presence of the connexin45 gap junctions since signaling through Ca^<2+>/calcineurin and NF-ATcl (originally named NF-ATc)was disrupted in the mutant hearts. These results indicate a requirement for gap junction intercellular channels during early cardiogenesis and hence implicate connexin in congenital heart diseases. This finding may be the first report to present the direct molecular mechanism of cell to cell communication through gap junction in the tissue development.