Pulses of RhoA Signaling Stimulate Actin Polymerization and Flow in Protrusions to Drive Collective Cell Migration

In animals, cells often move as collectives to shape organs, close wounds, or—in the case of disease—metastasize. To accomplish this, cells need to generate force to propel themselves forward. The motility of singly migrating cells is driven largely by an interplay between Rho GTPase signaling and the actin network. Whether cells migrating as collectives use the same machinery for motility is unclear. Using the zebrafish posterior lateral line primordium as a model for collective cell migration, we find that active RhoA and myosin II cluster on the basal sides of the primordium cells and are required for primordium motility. Positive and negative feedbacks cause RhoA and myosin II activities to pulse. These pulses of RhoA signaling stimulate actin polymerization at the tip of the protrusions and myosin II-dependent actin flow and protrusion retraction at the base of the protrusions, and deform the basement membrane underneath the migrating primordium. This suggests that RhoA-induced actin flow on the basal sides of the cells constitutes the motor that pulls the primordium forward, a scenario that likely underlies collective migration in other—but not all—contexts.在多细胞生物体内，细胞常以集体迁移的方式塑造器官、闭合创口，或是在疾病状态下发生肿瘤转移。为实现此类过程，细胞需要产生动力以推动自身向前运动。单个迁移细胞的运动能力主要由Rho GTP酶(Rho GTPase)信号通路与肌动蛋白网络(actin network)之间的相互作用所驱动。目前尚不清楚集体迁移的细胞是否采用相同的运动机制。本研究以斑马鱼后侧线原基(zebrafish posterior lateral line primordium)作为集体细胞迁移的研究模型，结果显示活化的RhoA与肌球蛋白II(myosin II)会在原基细胞的基底侧形成聚集，且该聚集对原基的运动能力至关重要。正负反馈环路可使RhoA与肌球蛋白II的活性呈现脉冲式波动。此类RhoA信号脉冲可刺激细胞突起尖端的肌动蛋白聚合，同时介导肌球蛋白II依赖的肌动蛋白流动与突起基部的收缩，并使迁移原基下方的基底膜(basement membrane)发生形变。上述结果表明，细胞基底侧由RhoA诱导产生的肌动蛋白流动，构成了推动原基向前迁移的核心动力来源，这一机制可能广泛存在于其他（但并非全部）集体细胞迁移的生理或病理场景中。