MicroRNA degradation by a conserved target RNA regulates animal behavior

Abstract

microRNAs (miRNAs) repress target transcripts through partial complementarity. By contrast, highly complementary miRNA-binding sites within viral and artificially engineered transcripts induce miRNA degradation in vitro and in cell lines. Here, we show that a genome-encoded transcript harboring a near-perfect and deeply conserved miRNA-binding site for miR-29 controls zebrafish and mouse behavior. This transcript originated in basal vertebrates as a long noncoding RNA (lncRNA) and evolved to the protein-coding gene NREP in mammals, where the miR-29-binding site is located within the 3' UTR. We show that the near-perfect miRNA site selectively triggers miR-29b destabilization through 3' trimming and restricts its spatial expression in the cerebellum. Genetic disruption of the miR-29 site within mouse Nrep results in ectopic expression of cerebellar miR-29b and impaired coordination and motor learning. Thus, we demonstrate an endogenous target-RNA-directed miRNA degradation event and its requirement for animal behavior.

The F‐box protein HAWAIIAN SKIRT is required for mimicry target‐induced microRNA degradation in Arabidopsis

“…Intriguingly, STTM not only relieves target RNAs from miRNA‐mediated inhibition, but also triggers miRNA destabilization (Yan et al ). Similar observations were also reported in animals (Bitetti et al ). However, the underlying mechanism remains elusive.…”

A Network of Noncoding Regulatory RNAs Acts in the Mammalian Brain

“…Natural TDMD triggers are found in some herpesviruses, which use this mechanism to promote degradation of specific host miRNAs (Cazalla et al, 2010; Libri et al, 2012; Marcinowski et al, 2012; Lee et al, 2013). In addition, a cellular transcript with TDMD activity limits miR-29b expression in cerebellar granule neurons and regulates behavior in mice and fish (Bitetti et al, 2018). …”

Interactions between short and long noncoding RNAs

“…Cyrano activity is associated with tailing and trimming of miR‐7, though tailing does not appear to contribute to trimming or miR‐7 degradation . Nrep is required for miR‐29b trimming (no substantial tailing was observed), and it is not clear if this trimming is needed for miR‐29b degradation .…”

“…There appear to be numerous parallels between the TDMD caused by Nrep and Cyrano. Both RNAs are quite abundant and predominantly cytoplasmic [96][97][98] and both contain unusually complementary sitesthe highly conserved region in Cyrano contains an 8mer pairing to the 5 0 of miR-7 and another 13 bases pairing to its 3 0 , thus pairing with all bases of miR-7 except 9 and 10 ( Fig. 3) [95,97].…”

“…Cyrano activity is associated with tailing and trimming of miR-7, though tailing does not appear to contribute to trimming or miR-7 degradation [97]. Nrep is required for miR-29b trimming (no substantial tailing was observed), and it is not clear if this trimming is needed for miR-29b degradation [96]. Interestingly, the main consequence of Cyrano loss is reduction in the levels of Cdr1as, a circular RNA, which as mentioned above harbors a large number of miR-7 sites.…”