Mechanisms of epithelial remodeling during organ development in C. elegans

线虫器官发育过程中上皮重塑的机制

• 批准号: 8326074
• 负责人: JAMES R PRIESS
• 金额: $ 41.74万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326074
• 关键词: Adhesions; Amaze; Apical; Basement membrane; Behavior; Biological Models; Biology; Caenorhabditis elegans; Cell Adhesion; Cell Shape; Cell-Cell Adhesion; Cells; Cellular biology; Deposition; Development; Developmental Biology; Disease; Dorsal; EVI1 gene; Embryonic Development; Epithelial; Epithelial Cells; Epithelium; Event; Genes; Genetic; Genetic Screening; Goals; Growth and Development function; Human; Integrin alpha Chains; Integrin alpha1; Invaded; Laminin; Lateral; Learning; Link; Location; Malignant Neoplasms; Myoepithelial; Neoplasm Metastasis; Organ; Pathway interactions; Pharyngeal structure; Process; Proteins; Proto-Oncogenes; Role; Shapes; Signal Pathway; Signal Transduction; Surface; System; Time; To specify; Tube; Wound Healing; cancer cell; cell assembly; cell behavior; cell motility; cell transformation; gene function; insight; interest; intraepithelial; migration; notch protein; positional cloning; research study; tool; trait

DESCRIPTION (provided by applicant): One of the fundamental steps in the formation of most organs is the assembly of cells into epithelial layers; simple epithelial cells share a common polarity, are linked by apical junctions and share a basal basement membrane. However, epithelia can undergo extensive remodeling during development, growth, or wounding, with constituent cells changing shape or moving. Some remodeling- specific behaviors of normal epithelia, such as the loss of cell adhesion, are reminiscent of cancer cells, the vast majority of which originate from epithelial cells. We recently discovered epithelial remodeling events in C. elegans that provide a system for understanding the genetic control of remodeling events, and that might provide insight into how epithelial-derived cells could be controlled in disease. The remodeling events in C. elegans transform two simple epithelial cells into ring-shaped cells. The events begin when a dorsal cell is signaled through the Notch pathway to become invasive. At the same time, a tract of laminin appears on the lateral interface between two, underlying ventral cells, perpendicular to the basal, basement membrane beneath these cells. The invasive cells spread onto the laminin tract, moving between the ventral cells until they reach the ventral basement membrane. Thus, the major epithelial cell behaviors in this system include (a) regulated changes in adhesion to neighboring cells and to the basement membrane, (b) cell invasion, (c) creation of invasion paths, and (d) reintegration into the surrounding epithelium following invasion. We exploit unique features of C. elegans biology that provide powerful tools to dissect the mechanisms involved in remodeling. We propose experiments to detect signaling between the invasive cells and the tract-forming cells, genetic screens to identify proteins required for the intraepithelial deposition of laminin, a reverse genetic approach to identify Notch targets required for invasion, and a system to study how the invasive cells are reintegrated into the epithelium.

描述（由申请人提供）：大多数器官形成的基本步骤之一是将细胞组装成上皮层；简单的上皮细胞具有共同的极性，通过顶端连接连接并共享基底膜。然而，上皮细胞在发育、生长或受伤过程中可能会经历广泛的重塑，其中组成细胞会改变形状或移动。正常上皮细胞的一些重塑特异性行为，例如细胞粘附的丧失，让人想起癌细胞，其中绝大多数源自上皮细胞。我们最近在秀丽隐杆线虫中发现了上皮重塑事件，这为理解重塑事件的遗传控制提供了一个系统，并且可能提供关于如何在疾病中控制上皮衍生细胞的见解。秀丽隐杆线虫的重塑事件将两个简单的上皮细胞转变为环形细胞。当背侧细胞通过Notch通路发出信号以变得具有侵入性时，这些事件就开始了。同时，在两个下方腹侧细胞之间的横向界面上出现一束层粘连蛋白，垂直于这些细胞下方的基底膜。侵袭性细胞扩散到层粘连蛋白束上，在腹侧细胞之间移动，直到到达腹侧基底膜。因此，该系统中的主要上皮细胞行为包括（a）与邻近细胞和基底膜粘附的调节变化，（b）细胞入侵，（c）入侵路径的创建，以及（d）入侵后重新整合到周围上皮中。我们利用线虫生物学的独特特征，为剖析参与重塑的机制提供了强大的工具。我们提出实验来检测侵袭性细胞和纤维束形成细胞之间的信号传导，进行遗传筛选来识别层粘连蛋白上皮内沉积所需的蛋白质，采用反向遗传方法来识别侵袭所需的Notch靶标，以及研究侵袭性细胞如何重新整合到上皮中的系统。