title: Dual regulation of miRNA biogenesis generates target specificity in neurotrophin-induced protein synthesis.
abstract: Control of translation is a fundamental source of regulation in gene expression. The induction of protein synthesis by brain-derived neurotrophic factor (BDNF) critically contributes to enduring modifications of synaptic function, but how BDNF selectively affects only a minority of expressed mRNAs is poorly understood. We report that BDNF rapidly elevates Dicer, increasing mature miRNA levels and inducing RNA processing bodies in neurons. BDNF also rapidly induces Lin28, causing selective loss of Lin28-regulated miRNAs and a corresponding upregulation in translation of their target mRNAs. Binding sites for Lin28-regulated miRNAs are necessary and sufficient to confer BDNF responsiveness to a transcript. Lin28 deficiency, or expression of a Lin28-resistant Let-7 precursor miRNA, inhibits BDNF translation specificity and BDNF-dependent dendrite arborization. Our data establish that specificity in BDNF-regulated translation depends upon a two-part posttranscriptional control of miRNA biogenesis that generally enhances mRNA repression in association with GW182 while selectively derepressing and increasing translation of specific mRNAs.
authors.affiliation: Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yu-Wen A
authors.initials: YW
authors.lastname: Huang
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Ruiz
authors.forename: Elizabeth C H
authors.initials: EC
authors.lastname: Eyler
authors.forename: Kathie
authors.initials: K
authors.lastname: Lin
authors.forename: Mollie K
authors.initials: MK
authors.lastname: Meffert
mesh_terms: D000818:Animals; D001324:Autoantigens; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D014176:Protein Biosynthesis; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000235:genetics; D043244:Ribonuclease III / Q000378:metabolism
chemical_list: D001324:Autoantigens; D019208:Brain-Derived Neurotrophic Factor; C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C571198:trinucleotide repeat containing 6a protein, mouse; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases