DRONC coordinates cell death and compensatory proliferation

Accidental cell death often leads to compensatory proliferation. In Drosophila imaginal discs, for example, -irradiation induces extensive cell death, which is rapidly compensated by elevated proliferation. Excessive compensatory proliferation can be artificially induced by “undead cells” that are kept alive by inhibition of effector caspases in the presence of apoptotic stimuli. This suggests that compensatory proliferation is induced by dying cells as part of the apoptosis program. Here, we provide genetic evidence that the Drosophila initiator caspase DRONC governs both apoptosis execution and subsequent compensatory proliferation. We examined mutants of five Drosophila caspases and identified the initiator caspase DRONC and the effector caspase DRICE as crucial executioners of apoptosis. Artificial compensatory proliferation induced by coexpression of Reaper and p35 was completely suppressed in dronc mutants. Moreover, compensatory proliferation after -irradiation was enhanced in drice mutants, in which DRONC is activated but the cells remain alive. These results show that the apoptotic pathway bifurcates at DRONC and that DRONC coordinates the execution of cell death and compensatory proliferation. Developing animal tissues have striking regenerative capacity. If a developing tissue is accidentally injured and a large number of cells undergo cell death, the final shape and size of the tissue are often invariant, owing to additional cell proliferation that compensates for the cell loss. The developing Drosophila larval imaginal disc is a tissue with extremely high regenerative capacity. Even when more than half of the cells are lost, the remaining cells undergo extra cell divisions and compensate for the loss (22). This “compensatory proliferation” is, at least in part, a local event that does not depend on the size control mechanism that governs the whole disc. For example, when apoptosis is locally induced by ectopic toxin expression, elevated cell proliferation is observed only around the site of apoptosis (40), suggesting that cells can perceive apoptosis occurring in the vicinity and undergo extra cell divisions until the original cell number is restored. Currently, little is known about how compensatory proliferation is regulated. One attractive hypothesis is that dying cells actively induce proliferation of the neighboring cells by secreting mitogens before they disappear. This hypothesis assumes that the noncell-autonomous induction of compensatory proliferation is a process that is under the control of the intracellular signaling pathway of apoptosis. According to this model, if cells could be stimulated to undergo apoptosis but artificially kept alive, the intracellular apoptosis signaling pathway would be activated