International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)


I8. N-cadherin-Mediated Cell Sorting in Chimeric Embryos

Igor Kostetskii1, Robert Moore2, Rolf Kemler2, and Glenn L. Radice1
1Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 USA, 2Department of Molecular Embryology, Max-Planck Institute fur Immunbiologie, Stubeweg 51, Freiburg, Germany

The sorting-out of experimentally intermixed embryonic cells and their subsequent reorganization into recognizable anatomical structures was elegantly demonstrated by Townes and Holtfreter nearly fifty years ago. Many explanations have been put forth to explain this sorting-out phenomena including the "site frequency model" proposed by Steinberg which predicts that adhesive differentials are due entirely to quantitative differences in the expression of a single, homophilic adhesion system.

Cadherins are calcium-dependent, homophilic cell adhesion molecules thought to be critical in controlling cell sorting during embryogenesis. We had previously shown that targeted inactivation of the N-cadherin gene caused severe cardiovascular defects leading to embryonic lethality. To further evaluate N-cadherin's role during morphogenesis, embryonic stem (ES) cells were isolated from N-cadherin+/- intercross matings. In order to distinguish the mutant and wild-type cells at the single cell level in situ, several independent ES cell lines were transfected with the marker gene, b-galactosidase. Here we report that chimeric embryos generated with N-cadherin-/- ES 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 detached aggregates of N-cadherin-/- myocardial cells in the heart lumen indicating that they are unable to maintain cell-cell contacts with N-cadherin-positive myocytes. This sorting-out phenomena is also 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/or increased mechanical stress associated with morphogenesis. Furthermore, our results confirm the prediction of the "site frequency model" that change in the expression of a single adhesion molecule is sufficient to allow cells to segregate from one another leading to formation of distinct embryonic structures.


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