Cell adhesion and signal transduction in Drosophila

细胞-细胞黏附在胚胎形成过程中的组织和器官组装、发育和伤口修复过程中的组织重塑以及成人组织维护中起着至关重要的作用。正常细胞粘附的破坏是肿瘤转移的关键步骤，也在遗传性和自身免疫性水疱疾病中起作用。对细胞粘附建立、维持和调节机制的理解将为正常细胞和发育过程提供基本的见解，也将帮助我们理解这些过程在疾病中是如何出错的。许多基本的细胞粘附机制存在于所有动物的共同祖先中，因此我们可以利用来自不同模式生物的见解来帮助推动我们领域的进步。我们建立了一个模型系统来研究细胞粘附和信号转导的耦合，使用果蝇。该系统中可用的工具使我们能够将非常强大的遗传方法与在完整动物背景下研究细胞生物学事件的能力结合起来，通常是实时的。这些分析的结果可以应用于人类细胞，以及在哺乳动物细胞和其他系统中进行的平行研究的结果，并纳入我们对果蝇的研究。这种协同作用比任何一个系统都能更快地推动进步。在过去的十年中，许多实验室的工作为我们提供了一个细胞-细胞粘附机制的静态模型，大致揭示了粘附连接（AJs）的钙粘蛋白和连环蛋白核心复合物如何介导粘附并将粘附连接连接到肌动蛋白细胞骨架。我们目前的挑战是扩展这项工作，并确定如何调节粘附，以允许在发育中的胚胎中发现不同的组织结构和细胞行为。在此，我们将重点讨论这一领域的三个悬而未决的问题，每个问题都为我们的具体目标之一提供了基础，具体目标如下：目的1：确定其他AJ蛋白的功能。目的2：定义AJs与肌动蛋白细胞骨架耦合的机制。目的3：表征AJ蛋白在细胞极性，纺锤体取向和MT组织中的新作用

Cell-cell adhesion plays a critical role in tissue and organ assembly during embryogenesis, tissue remodeling during development and wound repair, and tissue maintenance in the adult. Disruption of normal cell adhesion is a critical step in tumor metastasis, and also plays a role in inherited and autoimmune blistering diseases. An understanding of the mechanisms by which cell adhesion is established, maintained and regulated will thus provide fundamental insights into normal cell and developmental processes, and will also help us understand how these processes go awry in disease. Much of the basic cell adhesion machinery was present in the common ancestor of all animals, and thus we can make use of insights from different model organisms to help drive forward progress in our field. We developed a model system to study the coupling of cell adhesion and signal transduction, using the fruit fly Drosophila. The tools available in this system allow us to combine very powerful genetic approaches with the ability to study cell biological events in the context of the intact animal, often in real time. Results of these analyses can then be applied to human cells, and the results of parallel studies in mammalian cells and other systems incorporated into our own work in Drosophila. This synergy drives much more rapid progress than could be achieved in any one system. Work in many labs in the past ten years have provided us with a static model for the cell-cell adhesion machinery, revealing in outline how the core complex of cadherins and catenins at adherens junctions (AJs) mediates adhesion and link adhesive junctions to the actin cytoskeleton. Our current challenge is to extend this work and determine how adhesion is regulated to allow the diverse tissue architectures and cell behaviors found in the developing embryo. Here we focus on three unanswered questions in this area, each providing the basis for one of our Specific Aims, which are as follows; Aim 1: Define the function of additional AJ proteins. Aim 2: Define the mechanisms by which AJs are coupled to the actin cytoskeleton. Aim 3: Characterize novel roles of AJ proteins in cell polarity, spindle orientation and MT organization