CADHERIN-MEDIATED ADHESION AND PANCREATIC DEVELOPMENT

描述（由申请人提供）：胰腺起源于原始前肠的两个上皮褶皱。随着芽的生长，胰腺细胞类型的分化也随之进行。这种异质细胞群经历了广泛的细胞重组，导致外分泌和内分泌（朗格汉斯岛）部分的形成。为了完成形态发生事件，如上皮折叠和内分泌细胞组织成胰岛，表明细胞极性、细胞形状、细胞迁移、细胞分选和细胞重新聚集的调节，细胞粘附和细胞骨架重排被认为是重要的过程。因此，为了充分了解胰腺形态发生的机制，必须了解细胞-细胞粘附和肌动蛋白动力学如何协调发生。细胞粘附受体的钙粘蛋白家族在组织形态发生过程中负责选择性细胞-细胞粘附，并且已经提出GTPases的rho家族成员调节肌动蛋白重排。本研究项目的长期目标是了解钙粘蛋白介导的粘附和Rho gtpase在产生胰岛素的β细胞的发育、功能和维持中的作用。基因靶向实验的初步结果表明，n -钙粘蛋白是发育中的胰腺背芽建立所必需的。提出了四个具体目标：1)确定在嵌合胰腺中n -钙粘蛋白是否需要启动和/或维持细胞-细胞相互作用；2)利用基因靶向技术产生条件性n -钙粘蛋白突变，研究胰腺特异性基因消融对胰腺发育和功能的影响；3)确定胰腺背芽形成是否需要周围间质中n -钙粘蛋白的参与；4)探讨RhoA和Rac1在胰腺芽上皮折叠和β细胞功能中的功能作用。从这些实验中获得的知识将为理解胰腺如何从异质细胞群中组织起来提供一个分子框架，并可能为了解为什么产生胰岛素的β细胞在病理条件下功能障碍提供见解。

DESCRIPTION (provided by applicant): 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.