Molecular Cell
Volume 42, Issue 5, 10 June 2011, Pages 673-688
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Article
Reversible Inhibition of PSD-95 mRNA Translation by miR-125a, FMRP Phosphorylation, and mGluR Signaling

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Summary

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.

Highlights

► miR-125a reversibly inhibits PSD-95 mRNA translation and regulates spine morphology ► Phosphorylated FMRP forms an inhibitory complex with PSD-95 mRNA, AGO2, and miR-125a ► mGluR signals release of RISC from FMRP/PSD-95 mRNA complex to activate translation ► miR-125a loses its interaction with AGO2 and is deficient at Fmr1 KO synapses

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