Endogenous transcripts direct microRNA degradation in Drosophila, and this targeted degradation is required for proper embryonic development

MicroRNAs (miRNAs) typically direct degradation of their mRNA targets. However, some targets have unusual miRNA-binding sites that direct degradation of cognate miRNAs. Although this target-directed miRNA degradation (TDMD) is thought to shape the levels of numerous miRNAs, relatively few sites that endogenously direct degradation have been identified. Here, we identify six sites, five in mRNAs and one in a noncoding RNA named Marge, which serve this purpose in Drosophila cells or embryos. These six sites direct miRNA degradation without collateral target degradation, helping explain the effectiveness of this miRNA-degradation pathway. Mutations that disrupt this pathway are lethal, with many flies dying as embryos. Concomitant derepression of miR-3 and its paralog miR-309 appears responsible for some of this lethality, whereas the loss of Marge-directed degradation of miR-310 miRNAs causes defects in embryonic cuticle development. Thus, TDMD is implicated in the viability of an animal and is required for its proper development.