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

Tissue resilience and homeostasis rely on the tight coupling between cell proliferation, cell growth and cell death. This coupling is assumed to be based on compensatory proliferation, where local mitogenic signals and mechanical inputs generated by dying cells promote the proliferation of neighbouring cells. Compensatory proliferation was mostly studied in the Drosophila larval wing primordium (the wing disc) upon massive death induction in large domains, irradiation, surgical tissue ablation or upon genetic perturbation of apoptosis execution. Similar principles were also outlined in hydra, Drosophila midgut, Xenopus tadpole tail, Zebrafish tail or mammalian skin. However, it remains unclear whether the same mechanism operates during physiological programmed cell death or upon mild induction of apoptosis, especially in vivo. Moreover, these perturbations rely on ubiquitous induction of apoptosis or ablation of large domains, thus preventing quantitative characterisation of the spatial distribution 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 and compensate for mild induction of apoptosis. However, using spatial statistics we found surprisingly that local induction of death is not associated with any local increase in proliferation. Compensation is instead driven by JNK activation in dying cells which is required to reach the final tissue target size, most likely through the developmental delay triggered by the relaxin hormone Dilp8, although size compensation can still occur in the absence of Dilp8. These results suggest that a global response rather than local induction of proliferation contributes to tissue size compensation. Accordingly, while total tissue size is maintained despite local induction of apoptosis, this mechanism fails to correct the local reduction of cell number, hence modulating wing shape and proportions. Overall, this study opens novel perspectives on tissue size regulation and outlines the context-dependency of compensatory mechanisms.