Rescuing the N-cadherin knockout by cardiac-specific expression of N- or E-cadherin

Cell-cell adhesion mediated by some members of the cadherin family is essen tial for embryonic survival. The N-cadherin-null embryo dies during mid-ges tation, with multiple developmental defects, We show that N-cadherin-null e mbryos expressing cadherins using muscle-specific promoters, alpha- or beta -myosin heavy chain, are partially rescued. Somewhat surprisingly, either N-cadherin or E-cadherin was effective in rescuing the embryos. The rescued embryos exhibited an increased number of somites, branchial arches and the presence of forelimb buds; however, in contrast, brain development was sev erely impaired. In rescued animals, the aberrant yolk sac morphology seen i n N-cadherin-null embryos was corrected, demonstrating that this phenotype was secondary to the cardiac defect. Dye injection studies and analysis of chimeric animals that have both wild-type and N-cadherin-null cells support the conclusion that obstruction of the cardiac outflow tract represents a major defect that is likely to be the primary cause of pericardial swelling seen in null embryos. Although rescued embryos were more developed than nu ll embryos, they were smaller than wild-type embryos, even though the integ rity of the cardiovascular system appeared normal. The smaller size of resc ued embryos may be due, at least in part, to increased apoptosis observed i n tissues not rescued by transgene expression, indicating that N-cadherin-m ediated cell adhesion provides an essential survival signal for embryonic c ells, Our data provide in vivo evidence that cadherin adhesion is essential for cell survival and for normal heart development. Our data also show tha t E-cadherin can functionally substitute for N-cadherin during cardiogenesi s, suggesting a critical role for cadherin-mediated cell-cell adhesion, but not cadherin family member-specific signaling, at the looping stage of hea rt development.