Competitive elimination of ZO-1/ZO-2-deficient cells regulates epithelial barrier homeostasis

Summary Epithelia cover the body and form a barrier to segregate the internal body from the external environment. Epithelial tissues contact the external environment and are exposed to various stresses that are potentially deleterious for the epithelial barrier 1 . However, how focal epithelial barrier defects are detected and repaired to maintain epithelial barrier homeostasis remains poorly understood. We co-cultured ZO-1 / ZO-2 double-knockout (DKO) MDCK II cells, which lack tight junctions, with wild-type MDCK II cells, to understand how epithelial cells respond to focal epithelial barrier defects. When co-cultured with wild-type cells, ZO-1 / ZO-2 DKO cells were selectively eliminated by induction of apoptosis. The elimination depended on a purse-string-like contraction of supracellular actomyosin cables formed at the clone boundary, regulated by ROCK. Furthermore, Hippo signaling and adherens junctions in the surrounding wild-type cells were required to eliminate ZO-1 / ZO-2 DKO cells. These results demonstrate that selective elimination of ZO-1/ZO-2-deficient cells by cell competition regulates epithelial barrier homeostasis. In brief Otani et al. reveal that epithelial barrier homeostasis is regulated by cell competition-mediated elimination of ZO-1/ZO-2-deficient cells. Supracellular actomyosin cables form at the clone boundary and constrict in a purse-string-like manner to eliminate the ‘loser’ cells. Mechanosensing in the winning cells is required to eliminate the ‘loser’ cells. Highlights ZO-1/ZO-2-deficient cells are eliminated by cell competition Actomyosin cables form in the winning cells at the clone boundary A purse-string-like contraction of actomyosin cables compresses the losing cells Mechanosensing in the winning cells is important to eliminate the ‘loser’ cells