Molecular and Cellular Control of Collective Cell Migration.

摘要 在胚胎发育过程中，细胞经常成群移动，组装成组织， 机关它们被吸引梯度引导，并协调它们的迁移， 以有指导的方式。吸引剂梯度如何维持以及细胞如何迁移 各团体协调行动的情况尚不清楚。 为了解决这些问题，我们使用后侧线原基迁移， 以斑马鱼为模型。原基是一组约100个细胞，表达 趋化因子受体Cxcr4，并跟随Sdf1趋化因子的踪迹。我们已经用这种 系统，以显示原基产生一个Sdf1梯度跨越本身， 通过另一种Sdf1受体Cxcr7（一种趋化因子）将Sdf1隔离在其后部 清道夫受体在目标1中，我们将确定Sdf1水平如何由 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蛋白，并相互紧密粘附。在 目的2，我们将分析钙粘蛋白在协调集体迁移和使用中的作用 基于钙粘蛋白的张力传感器来测量细胞之间的张力， 原基我们的方法结合了斑马鱼原基的光学可及性 定量成像，胚胎和遗传操作，以及用于 趋化因子信号传导和张力，以提供对 细胞集体迁移的分子和细胞机制。我们预计 我们提出的研究将对细胞迁移领域产生两个广泛的影响。第一、 它们将提供如何调节引诱剂梯度的定量理解。 其次，他们将揭开迁移组织中细胞间粘附的机制。 这些见解是理解主要生物学和医学问题的关键， 胚胎发生、器官发生和癌症转移中的缺陷。

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.