Tight junction ZO proteins maintain tissue fluidity, ensuring efficient collective cell migration

Tight junctions are pivotal components of epithelial tissues connecting neighboring cells to provide protective barriers. However, explicit knowledge of their role during other crucial biological processes, such as collective cell migration, remains sparse. Here, the importance of the tight junction proteins ZO1 and ZO2 for epithelial migration is investigated employing video microscopy in conjunction with velocimetry, segmentation, cell tracking, and atomic force microscopy/spectroscopy. The results indicate that ZO proteins are necessary for fast and coherent migration. In particular, ZO1 and 2 loss induces actomyosin remodeling away from the central cortex towards the periphery of individual cells, resulting in altered viscoelastic properties. A tug-of-war emerges between two cell populations with distinct morphological and mechanical properties: 1) smaller and highly contractile cells with an outwards bulged apical membrane, and 2) larger, flattened cells, which, due to tensile stress, display a higher proliferation rate. In response, the cell density increases, leading to crowding-induced jamming and more small cells over time. These smaller cells are particularly immobile and therefore drive jamming. Knockout of only ZO1 induces a similar but less pronounced behavior. This study shows that ZO proteins are necessary for efficient collective cell migration by maintaining tissue fluidity and controlling proliferation.