ArticleHuman molecular genetics2017
FMRP-dependent Mdm2 dephosphorylation is required for MEF2-induced synapse elimination.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 31 citations in OpenAlex.
- Hyperfunction of PSD-95 leads to hyperexcitability and cognitive abnormalities in MEF2C haploinsufficiency.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- ATF4 Modulates Group 1 mGluR-Dependent molecular signaling, hippocampal plasticity and behavior.Molecular psychiatry · 2026Article
- E3 Ubiquitin Ligase Nedd4-2 Exacerbates Seizure-Induced Mitochondrial Defects in an Alzheimer's Disease Mouse Model.Journal of neurochemistry · 2026Article
- Neural Circuit Remodeling: Mechanistic Insights from Invertebrates.Journal of developmental biology · 2024Review
- EF1α-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice.Molecular psychiatry · 2024Article
- Hyperfunction of post-synaptic density protein 95 promotes seizure response in early-stage aβ pathology.EMBO reports · 2024Article
- A statistical method for image-mediated association studies discovers genes and pathways associated with four brain disorders.American journal of human genetics · 2024Article
- Synaptic cell adhesion molecules contribute to the pathogenesis and progression of fragile X syndrome.Frontiers in cellular neuroscience · 2024Review
- FMRP phosphorylation and interactions with Cdh1 regulate association with dendritic RNA granules and MEF2-triggered synapse elimination.Neurobiology of disease · 2023Article
- Transfer RNA-derived small RNAs (tsRNAs) in gastric cancer.Frontiers in oncology · 2023Review
- Amyloid beta induces Fmr1-dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2.Journal of cellular physiology · 2022Article
- A novel 3'tRNA-derived fragment tRF-Val promotes proliferation and inhibits apoptosis by targeting EEF1A1 in gastric cancer.Cell death & disease · 2022Article
- Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS.Nature reviews. Neuroscience · 2021Review
- ER stress-induced modulation of neural activity and seizure susceptibility is impaired in a fragile X syndrome mouse model.Neurobiology of disease · 2021Article
- Neuroprotective Effects Against Cerebral Ischemic Injury Exerted by Dexmedetomidine via the HDAC5/NPAS4/MDM2/PSD-95 Axis.Molecular neurobiology · 2021Article
- Hyperexcitability and Homeostasis in Fragile X Syndrome.Frontiers in molecular neuroscience · 2021Article
- Local Translation in Perisynaptic Astrocytic Processes Is Specific and Changes after Fear Conditioning.Cell reports · 2020Article
- Anxiolytic and Anxiogenic? How the Transcription Factor MEF2 Might Explain the Manifold Behavioral Effects of Oxytocin.Frontiers in endocrinology · 2020Review
- C2-lacking isoform of Nedd4-2 regulates excitatory synaptic strength through GluA1 ubiquitination-independent mechanisms.Journal of neurochemistry · 2019Article
- Novel roles of ER stress in repressing neural activity and seizures through Mdm2- and p53-dependent protein translation.PLoS genetics · 2019Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The Myocyte Enhancer Factor 2 (MEF2) transcription factors suppress an excitatory synapse number by promoting degradation of the synaptic scaffold protein, postsynaptic density protein 95 (PSD-95), a process that is deficient in the mouse model of Fragile X Syndrome, Fmr1 KO. How MEF2 activation results in PSD-95 degradation and why this is defective in Fmr1 KO neurons is unknown. Here we report that MEF2 induces a Protein phosphatase 2A (PP2A)-mediated dephosphorylation of murine double minute-2 (Mdm2), the ubiquitin E3 ligase for PSD-95, which results in nuclear export and synaptic accumulation of Mdm2 as well as PSD-95 degradation and synapse elimination. In Fmr1 KO neurons, Mdm2 is hyperphosphorylated, nuclear localized basally, and unaffected by MEF2 activation, which our data suggest due to an enhanced interaction with Eukaryotic Elongation Factor 1α (EF1α), whose protein levels are elevated in Fmr1 KO. Expression of a dephosphomimetic of Mdm2 rescues PSD-95 ubiquitination, degradation and synapse elimination in Fmr1 KO neurons. This work reveals detailed mechanisms of synapse elimination in health and a developmental brain disorder.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.