Potent degradation of neuronal miRNAs induced by highly complementary targets

MANUEL DE LA MATA; DIMOS GAIDATZIS; MIRELA VITANESCU; MICHAEL B STADLER; CORINNA WENTZEL; PETER SCHEIFFELE; WITOLD FILIPOWICZ; HELGE GROßHANS

Berna

Workshop; SWISS RNA WORKSHOP.; 2015

MicroRNAs(miRNAs) regulate target mRNAs by silencing them. Reciprocally, however, targetmRNAs can also modulate miRNA stability. Here, we uncover a remarkable efficacyof target RNA-directed miRNA degradation (TDMD) in rodent primary neurons.Coincident with degradation, and while still bound to Argonaute,targeted miRNAs are 3' terminally tailed and trimmed. Absolute quantificationof both miRNAs and their decay-inducing targets suggests that neuronal TDMD ismultiple turnover, and does not involve co-degradation of the target but rathercompetes with miRNA-mediated decay of the target. Moreover, mRNA silencing, butnot TDMD, relies on cooperativityamong multiple target sites to reach high efficacy. This knowledge can beharnessed for effective depletion of abundant miRNAs. Our findings bringinsight into a potent miRNA degradation pathway in primary neurons, whose TDMDactivity greatly surpasses that of non-neuronal cells and established celllines. Thus, TDMD may be particularly relevant for miRNA regulation in thenervous system.