Reversible Inhibition of PSD-95 mRNA Translation by miR-125a, FMRP Phosphorylation, and mGluR Signaling
Open accessAbstract
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.
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This de-repression increases abundance of regulatory proteins such as Arc, CaMKIIα, PSD95, and CaMKIIβ, setting up the spine for a binary decision between LTD and LTP.
“This in turn will increase the abundance of regulatory proteins such as Arc, CaMKIIα, PSD95, and CaMKIIβ (Darnell et al., 2011; Muddashetty et al., 2011; Niere et al., 2012; Park et al., 2008; Stefanovic et al., 2015), setting up the spine for a binary decision, to undergo LTD or LTP.”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Muddashetty et al., 2011
Stimulus-regulated phosphorylation or dephosphorylation of FMRP alters its ability to suppress mRNA translation.
“stimulus-regulated phosphorylation or dephosphorylation of FMRP alters its ability to suppress mRNA translation61,73–75.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [75]
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- Authors
- Muddashetty, R. S., Nalavadi, V. C., Gross, C., Yao, X., Xing, L., Laur, O., Warren, S. T., & Bassell, G. J.
- Affiliations
- Emory University (US)
- Corresponding author
- Bassell, Gary J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 42
- Issue
- 5
- Pages
- 673-688
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3115785
- OpenAlex
- W2071013424
- Cited by
- 364
- References
- 57
- Citations by year
- 2026: 8 · 2025: 3 · 2024: 14 · 2023: 13 · 2022: 24 · 2021: 24 · 2020: 32 · 2019: 24 · 2018: 23 · 2017: 23 · 2016: 25 · 2015: 29 · 2014: 31 · 2013: 39 · 2012: 37
- FWCI
- 24.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH085617, MH085617)
- National Institute on Drug Abuse (R21DA027080, DA027080)
- National Institute of Neurological Disorders and Stroke (P30NS055077)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD020521, R01HD020521, P30HD024064, R37HD020521)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- miR-125a, PSD-95, Argonaute 2, RNA-induced silencing complex, dendritic spine morphology, synapses, Fmr1 knockout, dendritic translation
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Dendrites, Humans, Membrane Proteins, Mice, Inbred C57BL, Phosphorylation, RNA, Messenger, Protein Biosynthesis, Signal Transduction, Eukaryotic Initiation Factor-2, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, MicroRNAs, Intracellular Signaling Peptides and Proteins, Mice, Rats, Guanylate Kinases, Fragile X Messenger Ribonucleoprotein 1, Gene Knockdown Techniques, Gene Knockout Techniques, Argonaute Proteins
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