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: 8161120
• 负责人: JAMES R PRIESS
• 金额: $ 41.25万
• 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/8161120
• 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. PUBLIC HEALTH RELEVANCE: Most human cancers are derived from epithelial cells, and some traits of cancer cells resemble unregulated, behaviors of normal epithelia that remodel during development, growth and wound repair. This project uses the model system C. elegans to identify, and understand the functions of, genes that normally control epithelial remodeling. These studies are expected to provide new insights into normal development, and may provide tools and strategies for controlling transformed epithelial cells.

描述（由申请人提供）：大多数器官形成的基本步骤之一是细胞组装成上皮层；简单上皮细胞具有共同的极性，由顶端连接连接，并共享一个基底膜。然而，上皮细胞在发育、生长或损伤过程中可经历广泛的重塑，其组成细胞可改变形状或移动。正常上皮细胞的一些重塑特异性行为，如细胞黏附的丧失，使人联想到癌细胞，而绝大多数癌细胞起源于上皮细胞。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，并可能为了解上皮源性细胞如何在疾病中被控制提供见解。秀丽隐杆线虫的重塑事件将两个简单的上皮细胞转化为环状细胞。当背侧细胞通过Notch通路发出信号成为侵袭性细胞时，事件就开始了。与此同时，层粘连蛋白束出现在两个腹侧细胞之间的横向界面上，垂直于这些细胞下面的基底膜。侵袭性细胞扩散到层粘连蛋白束，在腹侧细胞之间移动，直到到达腹侧基底膜。因此，该系统中上皮细胞的主要行为包括(a)对邻近细胞和基底膜粘附的调节变化，(b)细胞入侵，(c)创建入侵路径，以及(d)入侵后重新融入周围上皮。我们利用秀丽隐杆线虫生物学的独特特征，提供强大的工具来解剖参与重塑的机制。我们建议通过实验来检测侵袭细胞和束形成细胞之间的信号传导，通过遗传筛选来识别层粘连蛋白在上皮内沉积所需的蛋白质，通过反向遗传方法来识别侵袭所需的Notch靶点，并建立一个系统来研究侵袭细胞如何重新整合到上皮中。