MicroRNAs direct downregulation of target mRNAs. Sometimes, however, this regulatory paradigm inverts, and a target RNA triggers degradation of a microRNA. This target-directed microRNA degradation (TDMD) requires ZSWIM8. Zswim8 -/- mice exhibit reduced growth and perinatal lethality, accompanied by stabilization of >40 microRNAs. Nonetheless, studies of TDMD function in mammals have been limited because only two TDMD-triggering RNAs have been identified in mice. Here, we computationally identify and validate five new TDMD-triggering sites in mouse models. One site in Atp6v1g1 and two sites in Lpar4 direct degradation of miR-335-3p, showing that in mammals, two sites in the same transcript and multiple sites in different transcripts can collaborate to destabilize a microRNA. Moreover, sites in Plagl1 and Lrrc58 direct degradation of miR-322 and miR-503, respectively. Mice lacking the Plagl1 and Lrrc58 sites were smaller, demonstrating that target-directed degradation of miR-322 and miR-503 promotes growth. Both miR-335-3p and Plagl1 are maternally imprinted, implying their participation in parental conflict, but their corresponding triggers or target microRNA partners are not imprinted. Thus, 3' UTRs can participate in parental conflict not only by regulating protein production but also by engaging TDMD to access an additional layer of regulation within a network of imprinted and biallelic genes.
Keywords: Zswim8; gene regulation; imprinting; miRNA; target-directed miRNA degradation.
© 2026 Lin et al.; Published by Cold Spring Harbor Laboratory Press.