MiR-146a wild-type 3’ sequence identity is dispensable for proper innate immune function in vivo

The prevailing model of microRNA function is that the “seed” region (nucleotides 2-8) is typically sufficient to mediate target recognition and repression. However, numerous recent studies have challenged this model, either by demonstrating extensive 3’ pairing between physically defined miRNA-mRNA pairs or by showing in C. elegans that disrupted 3’ pairing can result in impaired function in vivo . To test the importance of miRNA 3’ pairing in a mammalian system in vivo , we engineered a mutant murine mir-146a allele in which the 5’ half of the mature microRNA retains its wild-type sequence, but the 3’ half has been altered to be anti-complementary. Mice homozygous or hemizygous for this mutant allele are phenotypically indistinguishable from wild-type controls and do not recapitulate any of the immunopathology previously described for mir-146a -null mice. Our results indicate that 3’ pairing is dispensable for the established myeloid function of this key mammalian microRNA. Summary Blurb 3’ sequence identity is dispensable for the established function of a mammalian miRNA in vivo .