Potent degradation of neuronal miRNAs induced by highly complementary targets.
MicroRNAs (miRNAs) regulate target mRNAs by silencing them. Reciprocally, however, target mRNAs can also modulate miRNA stability. Here, we uncover a remarkable efficacy of 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 quantification of both miRNAs and their decay-inducing targets suggests that neuronal TDMD is multiple turnover and does not involve co-degradation of the target but rather competes with miRNA-mediated decay of the target. Moreover, mRNA silencing, but not TDMD, relies on cooperativity among multiple target sites to reach high efficacy. This knowledge can be harnessed for effective depletion of abundant miRNAs. Our findings bring insight into a potent miRNA degradation pathway in primary neurons, whose TDMD activity greatly surpasses that of non-neuronal cells and established cell lines. Thus, TDMD may be particularly relevant for miRNA regulation in the nervous system.
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Manuel
M
de la Mata
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland Swiss Institute of Bioinformatics, Basel, Switzerland.
Dimos
D
Gaidatzis
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Mirela
M
Vitanescu
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland Swiss Institute of Bioinformatics, Basel, Switzerland University of Basel, Basel, Switzerland.
Michael B
MB
Stadler
Biozentrum, University of Basel, Basel, Switzerland.
Corinna
C
Wentzel
Biozentrum, University of Basel, Basel, Switzerland.
Peter
P
Scheiffele
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland University of Basel, Basel, Switzerland witold.filipowicz@fmi.ch helge.grosshans@fmi.ch.
Witold
W
Filipowicz
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland witold.filipowicz@fmi.ch helge.grosshans@fmi.ch.
Helge
H
Großhans
D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism*; D020029:Base Pairing; D001483:Base Sequence; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D061251:Primary Cell Culture; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D035683:MicroRNAs; D012333:RNA, Messenger
cooperativity; miRNA target; miRNA turnover; non‐templated RNA 3′‐end nucleotide additions; primary hippocampal neurons