title: Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling.
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.
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Muddashetty
authors.forename: Vijayalaxmi C
authors.initials: VC
authors.lastname: Nalavadi
authors.forename: Christina
authors.initials: C
authors.lastname: Gross
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Yao
authors.forename: Lei
authors.initials: L
authors.lastname: Xing
authors.forename: Oskar
authors.initials: O
authors.lastname: Laur
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Warren
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
mesh_terms: D000818:Animals; D060565:Argonaute Proteins; D003712:Dendrites / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D051528:Guanylate Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D060565:Argonaute Proteins; D000076122:Disks Large Homolog 4 Protein; D015852:Eukaryotic Initiation Factor-2; D051860:Fragile X Messenger Ribonucleoprotein 1; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; C526735:Ago2 protein, mouse; C501444:DLG4 protein, human; C501447:Dlg4 protein, mouse; C497684:Fmr1 protein, mouse; C527468:Mirn125 microRNA, mouse