Differential adhesion leads to segregation and exclusion of N-cadherin-deficient cells in chimeric embryos

Cadherin-mediated cell-cell interactions are thought to be critical in controlling cell sorting during embryogenesis. Here, we report that chimeric embryos generated with N-cadherin-deficient (N-cadherin(-/-)) embryonic stem cells develop further than embryos completely lacking N-cadherin only when the myocardium consists of N-cadherin-positive cells. Initially, the N-cadherin-negative and -positive cells mix together to form chimeric tissues; however, by embryonic day 9.5, the N-cadherin(-/-) cells segregate from the wild-type cells forming distinct aggregates. The chimeric embryos have large aggregates of N-cadherin(-/-) myocardial cells in the heart lumen, indicating that the cells are unable to maintain cell-cell contacts with N-cadherin-positive myocytes. This sorting-out phenomenon also is apparent in somites, neural tube, and developing brain where N-cadherin(-/-) cells form distinct lumenal structures. These studies demonstrate that N-cadherin-mediated adhesion is critical for maintaining cell-cell interactions in tissues undergoing active cellular rearrangements and increased mechanical stress associated with morphogenesis.