Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation
Open accessAbstract
Mutations or duplications in MECP2 cause Rett and Rett-like syndromes, neurodevelopmental disorders characterized by mental retardation, motor dysfunction, and autistic behaviors. MeCP2 is expressed in many mammalian tissues and functions as a global repressor of transcription; however, the molecular mechanisms by which MeCP2 dysfunction leads to the neural-specific phenotypes of RTT remain poorly understood. Here, we show that neuronal activity and subsequent calcium influx trigger the de novo phosphorylation of MeCP2 at serine 421 (S421) by a CaMKII-dependent mechanism. MeCP2 S421 phosphorylation is induced selectively in the brain in response to physiological stimuli. Significantly, we find that S421 phosphorylation controls the ability of MeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity-dependent induction of Bdnf transcription. These findings suggest that, by triggering MeCP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates nervous system maturation and that disruption of this process in individuals with mutations in MeCP2 may underlie the neural-specific pathology of RTT.
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MeCP2 is a transcriptional repressor.
“MeCP2 is a transcriptional repressor, and disruption of its function results in significant dendritic and synaptic dysregulation (Zhou et al., 2006).”
From The Environmental Neurotoxicant PCB 95 Promotes Synaptogenesis via Ryanodine Receptor-Dependent miR132 Upregulation (2014) · cites this paper as Zhou et al., 2006
Disruption of MeCP2 function results in significant dendritic and synaptic dysregulation.
“MeCP2 is a transcriptional repressor, and disruption of its function results in significant dendritic and synaptic dysregulation (Zhou et al., 2006).”
From The Environmental Neurotoxicant PCB 95 Promotes Synaptogenesis via Ryanodine Receptor-Dependent miR132 Upregulation (2014) · cites this paper as Zhou et al., 2006
MeCP2, which is mutated in Rett syndrome, controls excitatory synapse function and spine morphology in an activity-dependent manner.
“MeCP2, a transcriptional regulator that is mutated in Rett syndrome, controls the function of excitatory synapses and spine morphology in an activity-dependent manner43.”
From Dendritic spine pathology in neuropsychiatric disorders (2011) · cites this paper as [43]
Neuronal activity induces phosphorylation of MECP2 at Ser421 broadly across the genome.
“Neuronal activity induces the phosphorylation of MECP2 at Ser421 (refs 81–83) broadly across the genome”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [82]
MeCP2 is a methyl-CpG binding protein involved in regulating neuronal chromatin architecture and gene transcription, especially in response to neural activity and experience after birth.
“M ECP2 is a methyl-CpG binding protein implicated in the regulation of neuronal chromatin architecture and gene transcription (1)(2)(3)(4), especially in response to neural activity and experience during postnatal life (5,6).”
From MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex (2015) · cites this paper as [5]
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- Authors
- Zhou, Z., Hong, E. J., Cohen, S., Zhao, W.-N., Ho, H.-Y. H., Schmidt, L., Chen, W. G., Lin, Y., Savner, E., Griffith, E. C., Hu, L., Steen, J. A. J., Weitz, C. J., & Greenberg, M. E.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- Corresponding author
- Greenberg, Michael E.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2006-10
- Volume
- 52
- Issue
- 2
- Pages
- 255-269
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3962021
- OpenAlex
- W2149119305
- Cited by
- 877
- References
- 54
- Citations by year
- 2026: 26 · 2025: 32 · 2024: 24 · 2023: 25 · 2022: 36 · 2021: 42 · 2020: 30 · 2019: 29 · 2018: 46 · 2017: 46 · 2016: 57 · 2015: 49 · 2014: 69 · 2013: 65 · 2012: 62
- FWCI
- 22.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2517 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Helen Hay Whitney Foundation
- National Institutes of Health (NS048276, NS43491)
- Hertz Foundation
- Damon Runyon Cancer Research Foundation
- International Rett Syndrome Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- MeCP2, Rett syndrome, dendritic growth, dendritic spine maturation, CaMKII, neuronal activity, calcium influx, transcriptional repression, brain development
- MeSH terms
- Animals, Brain, Cell Differentiation, Neural Pathways, Synaptic Transmission, Neuronal Plasticity, Organ Culture Techniques, Organ Specificity, Phosphorylation, Serine, Rett Syndrome, Calcium-Calmodulin-Dependent Protein Kinases, Gene Expression Regulation, Developmental, Brain-Derived Neurotrophic Factor, Calcium Signaling, Dendritic Spines, Rats, Methyl-CpG-Binding Protein 2, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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