CADHERINS REGULATE AGGREGATION OF PANCREATIC BETA-CELLS IN-VIVO

It is thought that the cadherin protein family of cell adhesion molecu les regulates morphogenetic events in multicellular organisms, In this study we have investigated the importance of beta-cell cadherins for cell-cell interactions mediating the organization of endocrine cells i nto pancreatic islets of Langerhans. To interfere with endogenous cadh erin activity in beta-cells during pancreatic development, we overexpr essed a dominant negative mutant of mouse E-cadherin, lacking nearly a ll extracellular amino acids, in pancreatic beta-cells in transgenic m ice, Expression of the truncated E-cadherin receptor displaced both E- and N-cadherin from pancreatic beta-cells. As a result, the initial c lustering of beta-cells, which normally begins at 13.5-14.5 days postc oitum, was perturbed, Consequently, the clustering of endocrine cells into islets, which normally begins at 17.5-18 days postcoitum, was abr ogated, Instead, transgenic beta-cells were found dispersed in the tis sue as individual cells, while alpha-cells selectively aggregated into islet-like clusters devoid of beta-cells, Furthermore, expression of truncated E-cadherin in beta-cells resulted in an accumulation of beta -catenin in the cytoplasm, Thus, we have for the first time shown in v ivo that cadherins regulate adhesive properties of beta-cells which ar e essential for the aggregation of endocrine cells into islets.