Mechanisms of collective cell movement during embryonic heart development

生物学中一个突出的问题是细胞如何协调它们的运动。协调的细胞运动驱动组织发育和修复，也会导致疾病。细胞集体运动的一个共同特征是机械力的产生和传递。我的研究项目开发了新的定量显微镜和生物物理方法，其长期目标是建立协调活体动物细胞行为的物理和分子信号。我们的短期目标是确定果蝇（Drosophila melanogaster）心脏发育早期细胞运动和协调的机制。脊椎动物和无脊椎动物的心脏发育始于胚胎两侧的两组细胞的集体迁移，形成一个管。我们使用果蝇的心管形成来模拟集体细胞迁移，因为这是一个典型的过程，涉及两排52个心脏祖细胞（心脏母细胞），并且它允许实时成像和遗传，药理学和生物物理操作。我们发现成心细胞的运动不是连续的，而是由周期性的前进步骤组成。重要的是，我们发现动态细胞骨架蛋白网络在每个成心脏细胞的前部和后部之间周期性流动，每个周期对应一个细胞步骤。此外，我们还发现了一条由细胞骨架蛋白肌动蛋白形成的细胞超缆，在每排52个心脏细胞迁移时跨越它们。然而，控制细胞骨架流动和电缆的机制，以及这些网络对集体细胞迁移的贡献仍不清楚。

An outstanding question in biology is how cells coordinate their movements. Coordinated cell movements drive tissue development and repair, and also cause disease. A common feature of collective cell movements is the generation and transmission of mechanical forces. My research program develops novel quantitative microscopy and biophysical methods with the long-term objective of establishing the physical and molecular signals that coordinate cell behaviours in living animals. Our short-term goal for this proposal is to determine the mechanisms of cell movement and coordination during the early stages of heart development in the fruit fly Drosophila melanogaster. Heart development in vertebrates and invertebrates begins with the collective migration of two groups of cells from opposite sides of the embryo to form a tube. We use heart tube formation in Drosophila to model collective cell migration, as it is a stereotypical process involving two rows of 52 cardiac progenitors (cardioblasts) each, and it allows live imaging and genetic, pharmacological, and biophysical manipulations. We discovered that the movement of cardioblasts is not continuous, but rather consists of periodic steps forward. Importantly, we found that dynamic cytoskeletal protein networks flow periodically between the front and the back of each cardioblast, with each cycle corresponding with a cell step. In addition, we found a supracellular cable formed by the cytoskeletal protein actin and spanning the 52 cardioblasts in each row as they migrate. However, the mechanisms that govern cytoskeletal flows and cables, and the contributions of these networks to collective cell migration remain unclear. Here, we will (1) establish the role of dynamic cytoskeletal flows in cardioblast migration, and (2) define the contribution of the supracellular actin cable to collective cardioblast movements. To accomplish these aims, we will (3) develop quantitative microscopy, image analysis, and machine learning tools to monitor subcellular and supracellular cytoskeletal networks with high spatial and temporal resolution. Our tools will automate and thus accelerate the analysis of the images obtained, and will minimize human bias in the analysis. Our studies will reveal the mechanisms that control collective cell migration during heart tube formation in Drosophila. We will characterize a new mode of flow-driven cell movement, and a novel supracellular actin network that coordinates cardiac progenitor migration. The signals that regulate cytoskeletal dynamics are conserved across tissues and species. Thus, our findings will have direct implications for the general understanding of collective cell behaviours. Importantly, a group of talented trainees will also benefit from our research by receiving interdisciplinary training in cell and molecular biology, genetics, microscopy, image analysis and data science, all skills in high demand both in academic and industry settings.