ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
Isoform-specific toxicity of Mecp2 in postmitotic neurons: suppression of neurotoxicity by FoxG1.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 81 citations in OpenAlex.
- Probing DNA damage in Rett syndrome neurons uncovers a role for MECP2 regulation of PARP1.Stem cell reports · 2025Article
- Evidence of neuronal DNA damage in the brains of patients with Rett syndrome.Disease models & mechanisms · 2025Article
- Exploring the complexity of MECP2 function in Rett syndrome.Nature reviews. Neuroscience · 2025Review
- Up-Frameshift Factors from Phytopathogenic Fungi Play a Crucial Role in Nonsense-Mediated mRNA Decay.Journal of fungi (Basel, Switzerland) · 2025Article
- PLP1-Targeting Antisense Oligonucleotides Improve FOXG1 Syndrome Mice.International journal of molecular sciences · 2024Article
- Stroke Causes DNA Methylation atJournal of the American Heart Association · 2024Article
- Post-transcriptional regulation of the transcriptional apparatus in neuronal development.Frontiers in molecular neuroscience · 2024Review
- Methyl-CpG-Binding Protein 2 Emerges as a Central Player in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders.Cellular and molecular neurobiology · 2023Review
- Rett and Rett-related disorders: Common mechanisms for shared symptoms?Experimental biology and medicine (Maywood, N.J.) · 2023Review
- The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology.Cancers · 2023Review
- Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism.International journal of molecular sciences · 2023Review
- Differential Sensitivity of the Protein Translation Initiation Machinery and mTOR Signaling toCells · 2022Article
- Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2.Frontiers in pharmacology · 2022Article
- Review
- Proteomic and transcriptional changes associated with MeCP2 dysfunction reveal nodes for therapeutic intervention in Rett syndrome.Neurochemistry international · 2021Review
- FoxG1 regulates the formation of cortical GABAergic circuit during an early postnatal critical period resulting in autism spectrum disorder-like phenotypes.Nature communications · 2021Article
- Reviewing Evidence for the Relationship of EEG Abnormalities and RTT Phenotype Paralleled by Insights from Animal Studies.International journal of molecular sciences · 2021Review
- Article
- Regulation, diversity and function of MECP2 exon and 3'UTR isoforms.Human molecular genetics · 2020Review
- The Role of FoxG1 in the Inner Ear.Frontiers in cell and developmental biology · 2020Review
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
The methyl-CpG binding protein 2 (MeCP2) is a widely expressed protein, the mutations of which cause Rett syndrome. The level of MeCP2 is highest in the brain where it is expressed selectively in mature neurons. Its functions in postmitotic neurons are not known. The MeCP2 gene is alternatively spliced to generate two proteins with different N termini, designated as MeCP2-e1 and MeCP2-e2. The physiological significance of these two isoforms has not been elucidated, and it is generally assumed they are functionally equivalent. We report that in cultured cerebellar granule neurons induced to die by low potassium treatment and in Aβ-treated cortical neurons, Mecp2-e2 expression is upregulated whereas expression of the Mecp2-e1 isoform is downregulated. Knockdown of Mecp2-e2 protects neurons from death, whereas knockdown of the e1 isoform has no effect. Forced expression of MeCP2-e2, but not MeCP2-e1, promotes apoptosis in otherwise healthy neurons. We find that MeCP2-e2 interacts with the forkhead protein FoxG1, mutations of which also cause Rett syndrome. FoxG1 has been shown to promote neuronal survival and its downregulation leads to neuronal death. We find that elevated FoxG1 expression inhibits MeCP2-e2 neurotoxicity. MeCP2-e2 neurotoxicity is also inhibited by IGF-1, which prevents the neuronal death-associated downregulation of FoxG1 expression, and by Akt, the activation of which is necessary for FoxG1-mediated neuroprotection. Finally, MeCP2-e2 neurotoxicity is enhanced if FoxG1 expression is suppressed or in neurons cultured from FoxG1-haplodeficient mice. Our results indicate that Mecp2-e2 promotes neuronal death and that this activity is normally inhibited by FoxG1. Reduced FoxG1 expression frees MecP2-e2 to promote neuronal death.
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Registered trials
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.