ArticleNeurobiology of disease2023
FMRP phosphorylation and interactions with Cdh1 regulate association with dendritic RNA granules and MEF2-triggered synapse elimination.
Article in Neurobiology of disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 7 citations in OpenAlex.
- MCVAE-based multi-omic anomaly detection in Fragile X Syndrome.NAR molecular medicine · 2026Article
- The role of RNA binding proteins in cancer biology: A focus on FMRP.Genes & diseases · 2025Review
- Construction destruction: Contribution of dyregulated proteostasis to neurodevelopmental disorders.Current opinion in neurobiology · 2025Review
- RNA granules in flux: dynamics to balance physiology and pathology.Nature reviews. Neuroscience · 2024Review
- Synaptic cell adhesion molecules contribute to the pathogenesis and progression of fragile X syndrome.Frontiers in cellular neuroscience · 2024Review
- Crosstalk between ubiquitination and translation in neurodevelopmental disorders.Frontiers in molecular neuroscience · 2024Review
- Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex.Cell reports · 2023Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Fragile X Messenger Ribonucleoprotein (FMRP) is necessary for experience-dependent, developmental synapse elimination and the loss of this process may underlie the excess dendritic spines and hyperconnectivity of cortical neurons in Fragile X Syndrome, a common inherited form of intellectual disability and autism. Little is known of the signaling pathways that regulate synapse elimination and if or how FMRP is regulated during this process. We have characterized a model of synapse elimination in CA1 neurons of organotypic hippocampal slice cultures that is induced by expression of the active transcription factor Myocyte Enhancer Factor 2 (MEF2) and relies on postsynaptic FMRP. MEF2-induced synapse elimination is deficient in Fmr1 KO CA1 neurons, and is rescued by acute (24 h), postsynaptic and cell autonomous reexpression of FMRP in CA1 neurons. FMRP is an RNA binding protein that suppresses mRNA translation. Derepression is induced by posttranslational mechanisms downstream of metabotropic glutamate receptor signaling. Dephosphorylation of FMRP at S499 triggers ubiquitination and degradation of FMRP which then relieves translation suppression and promotes synthesis of proteins encoded by target mRNAs. Whether this mechanism functions in synapse elimination is not known. Here we demonstrate that phosphorylation and dephosphorylation of FMRP at S499 are both necessary for synapse elimination as well as interaction of FMRP with its E3 ligase for FMRP, APC/Cdh1. Using a bimolecular ubiquitin-mediated fluorescence complementation (UbFC) assay, we demonstrate that MEF2 promotes ubiquitination of FMRP in CA1 neurons that relies on activity and interaction with APC/Cdh1. Our results suggest a model where MEF2 regulates posttranslational modifications of FMRP via APC/Cdh1 to regulate translation of proteins necessary for synapse elimination.
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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.