Target-directed microRNA degradation regulates developmental microRNA expression and embryonic growth in mammals

In this study, Jones et al. investigated the biological role of miRNA regulation by target-directed microRNA degradation (TDMD) in mammals using mice with constitutive or conditional deletion of Zswim8, an essential TDMD factor, and provided new insight into the role of TDMD in embryonic organogenesis, particularly that of the heart and lungs. They further comprehensively profiled TDMD-regulated miRNAs across various embryonic tissues and provide insights into TDMD features of miRNA regulation, such as tissue-specific arm switching, tailing, trimming, and clustered transcription, during embryonic development. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play critical roles in development and disease. Target-directed miRNA degradation (TDMD), a pathway in which miRNAs that bind to specialized targets with extensive complementarity are rapidly decayed, has emerged as a potent mechanism of controlling miRNA levels. Nevertheless, the biological role and scope of miRNA regulation by TDMD in mammals remains poorly understood. To address these questions, we generated mice with constitutive or conditional deletion of Zswim8, which encodes an essential TDMD factor. Loss of Zswim8 resulted in developmental defects in the heart and lungs, growth restriction, and perinatal lethality. Small RNA sequencing of embryonic tissues revealed widespread miRNA regulation by TDMD and greatly expanded the known catalog of miRNAs regulated by this pathway. These experiments also uncovered novel features of TDMD-regulated miRNAs, including their enrichment in cotranscribed clusters and examples in which TDMD underlies "arm switching," a phenomenon wherein the dominant strand of a miRNA precursor changes in different tissues or conditions. Importantly, deletion of two miRNAs, miR-322 and miR-503, rescued growth of Zswim8-null embryos, directly implicating the TDMD pathway as a regulator of mammalian body size. These data illuminate the broad landscape and developmental role of TDMD in mammals.