Compressive stress drives morphogenetic apoptosis through lateral tension and Piezo

Tissues and organs constantly experience physical stress, including compression. Although the impact of overcrowding-induced compression on cell extrusion has been studied, its role in morphogenesis remains largely unexplored. Here, we show that natural compression exerted by the surrounding envelope on the developing Drosophila leg is required for proper morphogenesis. In this tissue, apoptosis, enriched in the future fold region, contributes to tissue folding by generating apical pulling forces. Yet only a subset of cells within the proapoptotic domain die, and how this pattern emerges was unknown. We found that natural compression regulates apoptosis, revealing compression as an integral part of its control during leg morphogenesis. Compression increases lateral cell tension and promotes apoptosis via the mechanosensor Piezo. Finally, interfering with cell cortex anchoring blocks this process. Altogether, our results indicate that compressive stress is actively integrated into the developmental program, driving both apoptosis and tissue folding.