The role of cell adhesion molecules in tissue formation and organogenesis

Sammanfattning: Cell adhesion molecules (CAMs) are cell surface glycoproteins that promote connection between two adjacent cells or between a cell and extra cellular matrix. These interactions are essential for tissue organisation during development and for the maintenance of tissue integrity in adult organisms. The aim of this thesis was to study the functional role of cadherins and N-CAM in tissue formation and organogenesis. To investigate the role of R-cadherin in tissue formation, we expressed R-cadherin constitutively in E-cad-/- ES cells (E-cad-/-/R-cad). When injected subcutaneously into syngenic hosts, ES cells form benign and solid teratomas. Under such conditions, injected wild type ES cells differentiated into a variety of tissues. In contrast, no organised structures were observed in tumors derived from E-cad-/- ES cells. However, in teratomas derived from E-cad-/-/R-cad ES cells, two tissue types appeared, namely striated muscle and epithelia. These results demonstrate that R-cadherin may be involved in formation of striated muscle and epithelium. In order to analyse the functional role of N-CAM in pancreatic islet cell type segregation, we employed N-CAM-deficient mice. In N-CAM mutant mice the normal localisation of a-cells in the periphery of the islets of Langerhans is lost, resulting in a disorganised islet cell architecture Furthermore, an increase in the clustering of cadherins, F-actin, and cell-cell junctions is observed, indicating enhanced cell polarisation and cadherin-mediated cell adhesion in these cells. Finally, degranulation of b-cells suggests that N-CAM is required for normal turnover of insulin-containing secretory granules. Taken together, we show for the first time in vivo that a cell adhesion molecule, in this case N-CAM, is involved in cell type segregation. Possible mechanisms may include changes in cadherin-mediated cell adhesion and cell polarity.During pancreatic ontogeny N-cadherin is initially expressed in the pancreatic mesenchyme and later in pancreatic endoderms, suggesting that it may regulate different aspects of pancreatic morphogeneis. Analysis of N-cadherin-deficient embryos revealed that these embryos suffer from a selective agenesis of the dorsal pancreas. Further analysis demonstrated that the mechanism for the lack of a dorsal pancreas involves an essential function of N-cadherin as a survival factor in the dorsal pancreatic mesenchyme.