Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling

Mol Cell. 2011 Jun 10;42(5):673-88. doi: 10.1016/j.molcel.2011.05.006.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Argonaute Proteins
  • Dendrites / metabolism
  • Disks Large Homolog 4 Protein
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • Fragile X Mental Retardation Protein / physiology
  • Gene Knockdown Techniques
  • Gene Knockout Techniques
  • Guanylate Kinases
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • MicroRNAs / physiology*
  • Phosphorylation
  • Protein Biosynthesis / physiology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction

Substances

  • Ago2 protein, mouse
  • Argonaute Proteins
  • DLG4 protein, human
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Eukaryotic Initiation Factor-2
  • Fmr1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • MicroRNAs
  • Mirn125 microRNA, mouse
  • RNA, Messenger
  • Receptors, Metabotropic Glutamate
  • Fragile X Mental Retardation Protein
  • Guanylate Kinases