The role of N-cadherin and S1P/S1P1 in pancreas development

University dissertation from Lund University, Faculty of Medicine

Abstract: Organogenesis of epithelial organs requires interaction between epithelial and mesenchymal tissues. During pancreas development, mesenchyme-derived structures induce specification, growth and differentiation of pancreatic epithelial cells. For instance, notochord, endothelial cells, and pancreatic mesenchyme are essential for the development of the pancreas. N-cadherin deficient-embryos suffer from dorsal pancreas agenesis due to apoptosis of the mesenchyme surrounding the pancreatic epithelium. N-cadherin-deficient embryos expressing N-cadherin or E-cadherin ectopically in the heart rescue dorsal pancreas formation, indicating that the phenotype is secondary to cardio-vascular defects. These results suggest that circulating factors are important for dorsal pancreas development. Here we identify a sphingolipid, sphingosine-1-phosphate, to be important for dorsal pancreas formation. S1P acts on receptors (S1P1, S1P2, and S1P3) expressed in the pancreatic mesenchyme, inducing mesenchymal growth. Studies on the S1P1 receptor knockout showed a reduced size of the dorsal pancreatic bud due to decreased proliferation of Pdx1+ cells. Other epithelial organs revealed growth defects. The lung epithelium had fewer branches and the stomach was smaller. This suggests that endothelial cells are essential for early development of the pancreatic epithelium. Since N-cadherin deficient embryos die at embryonic day E10, due to the cardio-vascular phenotype, we used a conditional N-cadherin deficient-mouse which was intercrossed with a Pdx-1-Cre driven transgenic line to generate a pancreas specific knockout. Our results indicate that N-cadherin neither is important for pancreas morphogenesis nor endocrine specification. This could be due to variable recombination efficiency of the Pdx-1-Cre line during development. However, mutant β-cells have fewer mature insulin secreting granules in the N-cadherin deleted islets indicating that N-cadherin is required for β-cell granule turnover.