Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice

Chen, Richard Z.; Akbarian, Schahram; Tudor, Matthew; Jaenisch, Rudolf

doi:10.1038/85906

Cited by 1,275Genetics and Neurodevelopmental DisordersEpigenetics and DNA MethylationNeuroscience and Neuropharmacology Research

Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice

Chen, Richard Z., Akbarian, Schahram, Tudor, Matthew, Jaenisch, Rudolf·2001·Nature Genetics

DOI 10.1038/85906

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Abstract

Mecp2 is an X-linked gene encoding a nuclear protein that binds specifically to methylated DNA (ref. 1) and functions as a general transcriptional repressor by associating with chromatin-remodeling complexes. Mecp2 is expressed at high levels in the postnatal brain, indicating that methylation-dependent regulation of gene expression may have a crucial role in the mammalian central nervous system. Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome (RTT, MIM 312750), a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that Mecp2-deficient mice exhibit phenotypes that resemble some of the symptoms of RTT patients. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. Mutant brains showed substantial reduction in both weight and neuronal cell size, but no obvious structural defects or signs of neurodegeneration. Brain-specific deletion of Mecp2 at embryonic day (E) 12 resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 deficiency in the CNS rather than in peripheral tissues. Deletion of Mecp2 in postnatal CNS neurons led to a similar neuronal phenotype, although at a later age. Our results indicate that the role of Mecp2 is not restricted to the immature brain, but becomes critical in mature neurons. Mecp2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome.

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Two alleles of Mecp2 are primarily used as mouse models of RTT: Mecp2tm1.1Bird, a null mutation, and Mecp2tm1.1Jae, which expresses low levels of a truncated protein.
“Two alleles of Mecp2 are primarily used as mouse models of RTT: Mecp2tm1.1Bird, a null mutation3, and Mecp2tm1.1Jae, which expresses low levels of a truncated protein32.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [32]
Loss of MeCp2 results in reduced brain weight and thinning of the neocortex in some mouse models.
“Loss of MeCp2 results in reduced brain weight [67, 126], with thinning of the neocortex described in some mouse models [115, 200, 302].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [67]

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Authors: Chen, R. Z., Akbarian, S., Tudor, M., & Jaenisch, R.
Affiliations: Whitehead Institute for Biomedical Research (US)
Massachusetts General Hospital (US)
Corresponding author: Jaenisch, Rudolf
ORCID: Chen, Richard Z.
Akbarian, Schahram
Tudor, Matthew
Jaenisch, Rudolf
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2001-03
Volume: 27
Issue: 3
Pages: 327-331
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/85906
OpenAlex: W1488115555
Cited by: 1,275
References: 29
Citations by year: 2026: 19 · 2025: 33 · 2024: 33 · 2023: 28 · 2022: 40 · 2021: 40 · 2020: 37 · 2019: 41 · 2018: 41 · 2017: 68 · 2016: 68 · 2015: 70 · 2014: 74 · 2013: 77 · 2012: 99
FWCI: 28.57
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: MeCP2, MeCP2 deficiency, Rett syndrome, DNA methylation, transcriptional repression, chromatin remodeling, neuronal dysfunction, mouse model
MeSH terms: Animals, Cell Differentiation, Central Nervous System, Chromosomal Proteins, Non-Histone, Disease Models, Animal, DNA-Binding Proteins, Female, Humans, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Neurons, Phenotype, Repressor Proteins, Rett Syndrome, CpG Islands, Cell Size, Mice, Methyl-CpG-Binding Protein 2

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Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice

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