While the pathways regulating apoptosis and cell extrusion are rather well described, what regulates the precise spatio-temporal distribution of cell elimination in tissues remains largely unknown. This is particularly relevant for epithelia with high rates of cell elimination, a widespread situation during embryogenesis and epithelial homeostasis, where concomitant death of neighbours could impair the maintenance of epithelial sealing. However, the extent to which epithelial tissues can cope with concomitant cell death, and whether any mechanism regulates such occurrence have never been explored so far. Here, using the Drosophila pupal notum (a single layer epithelium) and a new optogenetic tool to trigger caspase activation and cell extrusion, we first show that concomitant death of clusters of at least three cells is sufficient to transiently impair epithelial sealing. Such clustered extrusion was almost never observed in vivo, suggesting the existence of a mechanism preventing concomitant elimination of neighbours. Statistical analysis and simulations of cell death distribution in the notum highlighted a transient and local protective phase occurring near every dying cell. This protection is driven by a transient activation of ERK in the direct neighbours of extruding cells which reverts caspase activation and prevents elimination of cells in clusters. Altogether, this study demonstrates that the distribution of cell elimination in epithelia is an emerging property of transient and local feedbacks through ERK activation which is required to maintain epithelial sealing in conditions of high rate of cell elimination.

中文翻译：

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上皮密封的鲁棒性是由细胞消除驱动的局部ERK反馈的新兴特性

虽然调节凋亡和细胞挤出的途径已被很好地描述，但是调节组织中细胞消除的精确时空分布的机制仍然是未知的。这对于具有高细胞清除率的上皮细胞，在胚胎发生和上皮稳态中普遍存在的情况尤其重要，在这些情况下，邻居的伴随死亡可能会损害上皮密封的维持。然而，到目前为止，尚未探讨上皮组织可以应付伴随细胞死亡的程度，以及是否有任何机制调节这种情况的发生。在这里，使用果蝇p​​（单层上皮）和新的光遗传学工具触发caspase激活和细胞挤出，我们首先显示至少三个细胞簇的伴随死亡足以短暂损害上皮封闭。这种簇状挤出在体内几乎从未观察到，表明存在防止伴随消除邻居的机制。统计统计和模拟了细胞在死角中的分布，突显了每个垂死细胞附近都出现了短暂的局部保护相。这种保护作用是由在挤出细胞的直接邻居中短暂激活ERK来驱动的，该激活可恢复胱天蛋白酶的激活并阻止簇中细胞的清除。共，