microRNAs (miRNAs) repress target transcripts through partial complementarity. By contrast, highly complementary miRNAbinding 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.