The pancreas originates as two epithelial folds of the primitive foregut. Concomitant with growth of the buds pancreatic cell type differentiation proceeds. This heterogeneous cell population undergoes an extensive cell reorganization resulting in the formation of an exocrine and endocrine (islets of Langerhans) portion. To accomplish morphogenetic events such as epithelial folding and organization of endocrine cells into islets suggest regulation of cell polarity, cell shape, cell migration, cell sorting, and cell reaggregation, processes for which cell adhesion and cytoskeletal rearrangement are thought to be important. Thus, to fully understand the mechanism for pancreatic morphogenesis knowledge of how coordination of cell-cell adhesion and actin dynamics occurs must be achieved. The cadherin family of cell adhesion receptors is responsible for selective cell-cell adhesion during tissue morphogenesis, and it has been proposed that members of the Rho-family of GTPases regulate actin rearrangement. The long term goal of this research project is to understand the role of cadherin-mediated adhesion and Rho GTPases in the development, function, and maintenance of the insulin-producing Beta cells. Our initial results from gene targeting experiments indicate that N-cadherin is required for establishment of the dorsal bud of the developing pancreas.
Four specific aims are proposed: 1) To determine if N-cadherin is required to initiate and/or maintain cell-cell interactions in a chimeric pancreas; 2) To generate a conditional N-cadherin mutation using gene targeting technology and examine the consequences of pancreas-specific gene ablation on pancreatic development and function; 3) To determine if N-cadherin is required in the surrounding mesenchyme for pancreatic dorsal bud formation; 4) To examine the functional role of RhoA and Rac1 in epithelial folding of the pancreatic buds, and in Beta cell function. Knowledge gained from these experiments will provide a molecular framework for understanding how a pancreas is organized from a heterogeneous population of cells and possibly offer insights into why insulin-producing beta cells malfunction under pathological conditions.
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