Cadherin-mediated cell adhesion and tissue segregation: qualitative and quantitative determinants.

It is widely held that segregation of tissues expressing different cadherins results from cadherin-subtype-specific binding specificities. This belief is based largely upon assays in which cells expressing different cadherin subtypes aggregate separately when shaken in suspension. In various combinations of L cells expressing NCAM, E-, P-, N-, R-, or B-cadherin, coaggregation occurred when shear forces were low or absent but could be selectively inhibited by high shear forces. Cells expressing P- vs E-cadherin coaggregated and then demixed, one population enveloping the other completely. To distinguish whether this demixing was due to differences in cadherin affinities or expression levels, the latter were varied systematically. Cells expressing either cadherin at a lower level became the enveloping layer, as predicted by the Differential Adhesion Hypothesis. However, when cadherin expression levels were equalized, cells expressing P- vs E-cadherin remained intermixed. In this combination, "homocadherin" (E-E; P-P) and "heterocadherin" (E-P) adhesions must therefore be of similar strength. Cells expressing R- vs B-cadherin coaggregated but demixed to produce configurations of incomplete envelopment. This signifies that R- to B-cadherin adhesions must be weaker than either "homocadherin" adhesion. Together, cadherin quantity and affinity control tissue segregation and assembly through specification of the relative intensities of mature cell-cell adhesions.