La prise de décision concernant la mort des cellules épithéliales en aval des caspases effectrices in vivo

Epithelial cell death via apoptosis is fundamental to the development of organ shape, regulation of cell numbers, and prevention of cancer. As such, an individual cell's decision to die within an epithelium can have wide-ranging consequences for the tissue and the organism. Activation of the effector caspases, the terminal event in the highly conserved apoptotic signalling pathways, was previously considered a point-of-no-return in commitment to cell death. However, it is now clear that these enzymes also have non-apoptotic roles, and cell survival following effector caspase activation can be widespread. This indicates a layer of decision-making downstream of the effector caspases which remains to be fully understood in vivo. Using quantitative live imaging of the Drosophila pupal notum, combined with optogenetic perturbations and machine learning, we investigated commitment to apoptosis downstream of effector caspase activation. We identified a high level of cell-to-cell variability in the level of caspase activity required for commitment to apoptosis, as well as spatial domains of the tissue with high and low caspase sensitivity. Interestingly, we found that sublethal caspase activation events can prime cells for death for a few hours. Integrating information about past caspase activity was sufficient to explain much of the spatial pattern of caspase sensitivity as well as commitment to apoptosis at the single cell level. Sublethal caspase activation in clones was also sufficient to bias their subsequent elimination compared to wild-type neighbours, indicating that this priming effect could underpin a novel mode of physiological cell competition. Finally, we identified regions of the tissue which are intrinsically more caspase-sensitive regardless of prior activation, and we profiled the transcription of cells in one of these regions to identify genes that could be screened as candidate caspase sensitivity regulators. Together, our results indicate a new layer of apoptosis regulation which can be influenced by prior sublethal caspase activation and may also be modulated by other genetic factors that remain to be characterised.