SRP181199 PRJNA516456 GSE125473 Mir-146a wild-type 3' sequence identity is dispensable for proper innate immune function in vivo (miRNA-Seq) A long-prevailing model has held that the “seed” region (nucleotides 2-8) of a microRNA is typically sufficient to mediate target recognition and repression. However, numerous recent studies, both within the context of defining miRNA/target pairs by direct physical association and by directly assessing this model in vivo in C. elegans have brought this model into question. To test the importance of miRNA 3' pairing in vivo, in a mammalian system, we engineered a mutant murine mir-146a allele in which the 5' half of the mature microRNA retains the sequence of the wild-type mir-146a but the 3' half has been altered to be anti-complementary to the wild-type miR-146a sequence. 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 strongly support the conclusion that 3' pairing is dispensable in the context of the function of a key mammalian microRNA. Overall design: Small-RNA expression profiling of resting bone marrow derived macrophages (BMDMs) from miR-146 wild-type (WT), knock-out (KO) and non-seed swap (3'F) mice GSE125473 pubmed 30777858 parent_bioproject PRJNA516453