Abstract
The molecular mechanism for how RISC and microRNAs selectively and reversibly regulate mRNA translation in response to receptor signaling is unknown but could provide a means for temporal and spatial control of translation. Here we show that miR-125a targeting PSD-95 mRNA allows reversible inhibition of translation and regulation by gp1 mGluR signaling. Inhibition of miR-125a increased PSD-95 levels in dendrites and altered dendritic spine morphology. Bidirectional control of PSD-95 expression depends on miR-125a and FMRP phosphorylation status. miR-125a levels at synapses and its association with AGO2 are reduced in Fmr1 KO. FMRP phosphorylation promotes the formation of an AGO2-miR-125a inhibitory complex on PSD-95 mRNA, whereas mGluR signaling of translation requires FMRP dephosphorylation and release of AGO2 from the mRNA. These findings reveal a mechanism whereby FMRP phosphorylation provides a reversible switch for AGO2 and microRNA to selectively regulate mRNA translation at synapses in response to receptor activation.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Argonaute Proteins
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Dendrites / metabolism
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Disks Large Homolog 4 Protein
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Eukaryotic Initiation Factor-2 / metabolism
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Fragile X Mental Retardation Protein / genetics
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Fragile X Mental Retardation Protein / metabolism*
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Fragile X Mental Retardation Protein / physiology
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Gene Knockdown Techniques
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Gene Knockout Techniques
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Guanylate Kinases
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Humans
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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MicroRNAs / genetics
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MicroRNAs / metabolism
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MicroRNAs / physiology*
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Phosphorylation
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Protein Biosynthesis / physiology
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, Metabotropic Glutamate / metabolism*
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Signal Transduction
Substances
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Ago2 protein, mouse
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Argonaute Proteins
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DLG4 protein, human
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Eukaryotic Initiation Factor-2
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Fmr1 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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MicroRNAs
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Mirn125 microRNA, mouse
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RNA, Messenger
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Receptors, Metabotropic Glutamate
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Fragile X Mental Retardation Protein
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Guanylate Kinases