A global response contributes to tissue size robustness upon local induction of apoptosis

Tissue resilience requires tight coupling between cell proliferation, growth, and death.^1,2,3,4It is assumed to be based on compensatory proliferation, where local mitogenic signals and mechanical inputs generated by dying cells promote the proliferation of neighboring cells.^{5,6,7,8,9,10,11} Compensatory proliferation was mostly studied in the Drosophila larval wing primordium (the wing disc) upon massive death induction in large domains,¹² irradiation,^13,14 surgical tissue ablation,^15,16 or genetic perturbation of apoptosis execution.^8,17 Similar principles were outlined in hydra,¹⁸Drosophila midgut,¹⁹Xenopus tadpole tail,²⁰ zebrafish tail,²¹ or mammalian skin.²² However, it remains unclear whether the same mechanism operates during physiological or mild-induced apoptosis, especially in vivo. Moreover, large-scale perturbations used so far have prevented quantitative spatial characterization of compensation. Here, we use the Drosophila larval wing disc to study the impact of local induction of apoptosis on tissue size and proliferation pattern. We first confirmed that the wing could recover its final size despite mild induction of apoptosis. However, using spatial statistics, we surprisingly found that local induction of death is not associated with any local increase in proliferation. Compensation is instead driven by c-Jun N-terminal kinase (JNK) activation in dying cells, which is required to reach the final tissue target size, most likely triggering a global compensatory response. Accordingly, while total wing size can be corrected despite local induction of apoptosis, the relative local reduction of cell number is not, hence modulating wing shape and proportions. Overall, this study opens novel perspectives on tissue size regulation and outlines the context dependency of compensatory mechanisms.