Molecular and Cellular Control of Collective Cell Migration.

摘要 在胚胎发育期间，细胞经常成群移动以组装成组织和 器官。它们由吸引剂梯度引导，并协调它们的迁移以移动 以定向的方式。如何保持吸引剂梯度以及细胞如何迁移 组织协调他们的行动尚不清楚。 为了解决这些问题，我们使用后侧线原基移位术。 斑马鱼作为模特。原基是由大约100个细胞组成的群体，表达 趋化因子受体CXCR4和跟随SDF1趋化因子的踪迹。我们用过这个 系统显示原基通过以下方式在其自身上生成SDF1渐变 通过另一种趋化因子SDF1受体CXCR7将SDF1隔离在其后部 清道夫受体。在目标1中，我们将确定SDF1级别如何由 趋化因子清除受体CXCR7使用我们开发的SDF1信号传感器。 原基中的细胞也表达钙粘附素，并相互紧密粘连。在……里面 目的2，我们将分析钙粘附素在协调集体迁移和使用中的作用 基于钙粘附素的张力传感器，用于测量细胞之间的张力 原基植物。我们的方法结合了斑马鱼原基的光学可及性 具有定量成像、胚胎和遗传操作以及新型传感器 趋化因子信号和紧张力提供对 集体细胞迁移的分子和细胞机制。我们期待着 我们提议的研究将对细胞迁移领域产生两个广泛的影响。第一, 它们将提供对引诱剂梯度如何调节的定量理解。 其次，他们将揭开迁移组织中细胞间黏附的机制。 这些见解是理解重大生物学和医学问题的关键，包括 胚胎发生、器官发生和癌症转移方面的缺陷。

ABSTRACT During embryonic development, cells often move in groups to assemble into tissues and organs. They are guided by attractant gradients and coordinate their migration to move in a directed manner. How attractant gradients are maintained and how cells in migrating groups coordinate their movements is unclear. To address these questions, we use the posterior lateral line primordium migration in zebrafish as a model. The primordium is a group of about 100 cells, which express the chemokine receptor Cxcr4 and follow a trail of Sdf1 chemokine. We have used this system to show that the primordium generates an Sdf1 gradient across itself by sequestering Sdf1 in its rear through the alternate Sdf1 receptor Cxcr7, a chemokine scavenger receptor. In Aim 1, we will determine how Sdf1 levels are controlled by the chemokine clearance receptor Cxcr7 using an Sdf1 signaling sensor that we developed. The cells in the primordium also express cadherins and adhere to each other tightly. In Aim 2, we will analyze the role of cadherins in coordinating collective migration and use cadherin-based tension sensors to measure the tension forces between the cells in the primordium. Our approach combines the optical accessibility of the zebrafish primordium with quantitative imaging, embryonic and genetic manipulations, and novel sensors for chemokine signaling and tension forces to provide a quantitative understanding of the molecular and cellular mechanisms underlying collective cell migration. We anticipate that our proposed studies will have two broad impacts on the field of cell migration. First, they will provide a quantitative understanding of how attractant gradients are regulated. Second, they will unravel the mechanics of cell-cell adhesion in a migrating tissue. These insights are key to understanding major biological and medical problems including defects in embryogenesis, organogenesis, and cancer metastasis.