Distinct roles of clustered MicroRNAs miR-286 and miR-6 in JNK activation critical to apoptosis-induced proliferation in Drosophila

Apoptosis-induced proliferation (AiP) is an evolutionarily conserved process implicated in tissue regeneration and tumorigenesis. Studies in Drosophila have identified activation of the stress response molecule c-Jun N-terminal kinase (JNK) as a critical step in mediating AiP. Interestingly, JNK activation can be further amplified to drive tissue overgrowth during this process. However, the mechanisms that coordinate the initial activation of JNK and its subsequent amplification remain poorly understood. In this study, we identified distinct functions for two members of the microRNA cluster miR-309/3/286/4/5/6 − 1/6 − 2/6 − 3, specifically miR-286 and miR-6, in regulating JNK signaling during AiP. We found that miR-6 promoted the initial activation of JNK, whereas miR-286 inhibited its amplification. During AiP, the expression of miR-286 was reduced, and we identified Calx, a gene encoding a sodium/calcium exchanger involved in intracellular calcium homeostasis, as a direct target of miR-286. Loss of miR-286 led to increased Calx expression and enhanced JNK amplification. Genetically, these promoted AiP through calcium signaling. Together, our findings revealed a microRNA-based regulatory mechanism that coordinates different stages of JNK activation during AiP.