Tissue mechanics and systemic signaling safeguard epithelial tissue against spindle misorientation

Multicellular organisms possess conserved safeguard mechanisms that ensure the maintenance of tissue integrity. Exploring these mechanisms has proven instrumental in understanding how tissues robustly develop and prevent tumor initiation. Here, we investigate how epithelial tissues preserve their architecture and cell number in the face of spindle mis-orientation. Spindle mis-orientation, due to the lack of spindle pulling forces, centrosomes, or mitotic rounding, can cause epithelial cells to be mispositioned within or outside the tissue, leading to significant cell loss. By inducing spindle mis-orientation in Drosophila epithelial tissue, we first found that acentrosomal microtubules and cell contractility prevent excessive epithelial cell loss by enabling mispositioned cells to reintegrate into the epithelium. However, this mechanism alone is insufficient to maintain the total epithelial cell number. We uncovered that epithelial mechanics and cell size sensing monitor and compensate for epithelial cell loss predominantly by reducing physiological apoptosis through Hippo/YAP signaling. Lastly, we found that systemic 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.