Contraction forces developed by cardiomyocytes are transmitted across the plasma membrane through end-to-end connections between the myocytes, called intercalated disks, which enable the coordinated contraction of heart muscle. A component of the intercalated disk, the adherens junction, consists of the cell adhesion molecule, N-cadherin. Embryos lacking N-cadherin die at mid-gestation from cardiovascular abnormalities. We have evaluated the role of N-cadherin in cardiomyogenesis using N-cadherin-null mouse embryonic stem (ES) cells grown as embryoid bodies (EBs) in vitro. Myofibrillogenesis, the spatial orientation of myofibers, and intercellular contacts including desmosomes were normal in N-cadherin-null ES cell-derived cardiomyocytes. The effect of retinoic acid (RA), a stage and dose-dependent cardiogenic factor, was assessed in differentiating ES cells. all-trans (at) RA increased the number of ES cell-derived cardiomyocytes by approximately 3-fold (at 3 x 10(-9) M) in wt EBs. However, this effect was lost in N-cadherin-null EBs. In the presence of supplemented at-RA, the emergence of spontaneously beating cardiomyocytes appeared to be delayed and slightly less efficient in N-cadherin-null compared with wt and heterozygous EBs (frequencies of EBs with beating activity at 5 days: 54+/-18% vs. 96+/-0.5%, and 93+/-7%, respectively; peak frequencies of EBs with beating activity: 83+/-8% vs. 96+/-0.5% and 100%, respectively). In conclusion, cardiomyoyctes differentiating from N-cadherin-null ES cells in vitro show normal myofibrillogenesis and intercellular contacts, but impaired responses to early cardiogenic effects mediated by at-RA. These results suggest that N-cadherin may be essential for RA-induced cardiomyogenesis in mouse ES cells in vitro.

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beating myofibrillogenesis and intercellular contacts ncadherin cells atra coordinated contraction of heart rainduced cardiomyogenesis cardiogenic ebs spatial orientation of myofibers intercalated cell adhesion endtoend connections cardiomyocytes desmosomes abnormalities cellderived

R, Bugorsky J-C, Perriard G, Vassalli,.N-cadherin is essential for retinoic acid-mediated cardiomyogenic differentiation in mouse embryonic stem cells.. 51 (3),181-92.

R, Bugorsky J-C, Perriard G, Vassalli,"N-cadherin is essential for retinoic acid-mediated cardiomyogenic differentiation in mouse embryonic stem cells." 51

R, Bugorsky J-C, Perriard G, Vassalli,"N-cadherin is essential for retinoic acid-mediated cardiomyogenic differentiation in mouse embryonic stem cells."