Tissue mechanics and systemic signaling safeguard epithelial tissue against spindle misorientation

Multicellular organisms possess conserved safeguard mechanisms maintaining tissue integrity. Exploring these mechanisms is instrumental in understanding how tissues robustly develop and prevent tumor initiation. Here, we investigate how epithelial tissues preserve their architecture and cell number upon spindle misorientation. Spindle misorientation can cause epithelial cells to be mispositioned within or outside the tissue, leading to significant cell loss. By inducing spindle misorientation in Drosophila epithelial tissue, we found that non-centrosomal microtubules and cell contractility prevent excessive cell loss by promoting the reintegration of mispositioned cells into the epithelium. Additionally, we demonstrated that tissue mechanics and cell-size sensing monitor and compensate for cell loss predominantly by reducing physiological apoptosis through Hippo/YAP signaling. Lastly, systemic tumor necrosis factor (TNF) signaling protects the organism by eliminating potentially harmful non-reintegrating cells. Overall, our results delineate the complementary roles of mechanics and systemic signaling in controlling cell number and position at both tissue and organismal levels.