Pressure and curvature control of the cell cycle in epithelia growing under spherical confinement

Morphogenesis requires spatiotemporal regulation of proliferation, both by biochemical and mechanical cues. In epithelia, this regulation is called contact inhibition of proliferation, but disentangling biochemical from mechanical cues remains challenging. Here, we show that epithelia growing under confinement accumulate pressure that inhibits proliferation above a threshold value. During growth, epithelia spontaneously buckle, and cell proliferation is transiently reactivated within the fold. Reactivation of proliferation within folds correlated with the local reactivation of the mechano-sensing YAP/TAZ pathway. At late time points, when the pressure is highest, β-catenin activity increases. The threshold pressure increases when β-catenin is overactivated and decreases when β-catenin is inhibited. Altogether, our results suggest that different mechanical cues resulting from pressure inhibition of proliferation are at play through different mechano-sensing pathways: the β-catenin pathway sustains cell division under high pressure, and the YAP pathway senses local curvature.