DRONC Coordinates Cell Death and Compensatory Proliferation

Abstract

Accidental cell death often leads to compensatory proliferation. In Drosophila imaginal discs, for example, γ-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 γ-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.

Supplemental material for this article may be found at http://mcb.asm.org/.

We thank the Bloomington Drosophila Stock Center; the Developmental Studies Hybridoma Bank; GenExel, Inc.; Kimberly McCall; Tetsuya Tabata; and Takaomi Saido for reagents. We thank Hoshio Eguchi for assistance with γ-irradiation. We thank members of the Miura and Hiromi laboratories for helpful discussions.

This study was supported by grants from the Japanese Ministry of Education, Science, Sports, Culture, and Technology (to M.M. and Y.H.); the CREST program of the Japan Science and Technology Agency (to Y.H.); and the Cell Science Research Foundation (to M.M.).