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Cited by 253Genetics and Neurodevelopmental DisordersEpigenetics and DNA MethylationGenetic Neurodegenerative Diseases

Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus

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Ben-Shachar, Shay, Chahrour, Maria, Thaller, Christina, Shaw, Chad A., Zoghbi, Huda Y.·2009·Human Molecular Genetics
DOI 10.1093/hmg/ddp181PMC PMC2694691
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Abstract

A group of post-natal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased copy number of the gene causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however the gene expression changes observed in the hypothalamus of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression, given that the majority of genes are downregulated upon loss of MeCP2 and upregulated in its presence. To determine if this dual role of MeCP2 extends beyond the hypothalamus, we studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-Tg mice, modeling RTT and MECP2 duplication syndrome, respectively. We found that abnormal MeCP2 dosage causes alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MeCP2 as a modulator that can both increase and decrease gene expression. Interestingly, many of the genes altered in the cerebellum, particularly those increased by the presence of MeCP2 and decreased in its absence, were similarly altered in the hypothalamus. Our data suggest that either gain or loss of MeCP2 results in gene expression changes in multiple brain regions and that some of these changes are global. Further delineation of the expression pattern of MeCP2 target genes throughout the brain might identify subsets of genes that are more amenable to manipulation, and can thus be used to modulate some of the disease phenotypes.

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  • Microarray analysis of cerebella from 6-week-old Mecp2 null mice and mice with increased expression of human MECP2 showed a 28% fall and a 21% increase, respectively, in the relative mRNA level for Cyp46a1.

    “One study using microarray analysis of cerebella from 6-week-old Mecp2 null mice, as well as mice with an increased expression of human MECP2, showed a 28% fall versus a 21% increase in the relative mRNA level for Cyp46a1 in the knockouts and transgenic mice, respectively (Ben-Shachar et al., 2009).”

    From Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis (2017) · cites this paper as Ben-Shachar et al., 2009

    The Results section, “Cerebellar gene expression changes in mouse models of MeCP2 disorders” (page unavailable), confirms microarray analysis of cerebella from 6-week-old Mecp2-null and human MECP2-overexpressing mice. Our copy does not report the claimed 28% decrease or 21% increase for Cyp46a1; a search for Cyp46a1 found no matching passage. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Elimination of MeCP2 affects the expression of a profound number of pathways in the CNS, making it difficult to pinpoint which pathways play a key role in RTT pathology.

    “While Mecp2 mutant mice are an excellent model for RTT, elimination of MeCP2 affects the expression of a profound number of pathways in the CNS, making it difficult to pinpoint which ones play a key role in pathology [77,89,90].”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [89]

    The Discussion reports hundreds of altered genes in the cerebellum and thousands in the hypothalamus, including genes involved in several neuronal processes. This supports widespread expression changes in brain regions of MeCP2-disorder mouse models, but the paper does not establish that a profound number of pathways are affected or say that this makes it difficult to identify which pathways drive RTT pathology. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • MeCP2 may be defined as a transcriptional modulator.

    “Altogether, multiple studies suggest that genes can be activated or repressed by MeCP2, depending upon the cellular context [77,89,90], suggesting that MeCP2 may be defined as a transcriptional modulator.”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [89]

  • Mecp2 KO mice exhibit a reduced rate of brain cholesterol biosynthesis, downregulation of key metabolic enzymes, and decreased levels of cholesterol precursors, despite accumulation of cholesterol in the brain.

    “In particular, Mecp2 KO mice exhibit a reduced rate of brain cholesterol biosynthesis, together with the downregulation of key metabolic enzymes and decreased levels of cholesterol precursors, despite the accumulation of cholesterol in the brain (Ben-Shachar et al., 2009;Buchovecky et al., 2013b;Lütjohann et al., 2018;Urdinguio et al., 2008Urdinguio et al., , 2008;;Villani et al., 2016).”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Ben-Shachar et al., 2009

    The Results section on cerebellar gene expression reports altered transcripts in Mecp2-null mice, but does not identify cholesterol-metabolism enzymes or measure cholesterol synthesis, precursors, or accumulation. Searches of our copy for cholesterol, sterols, biosynthesis, and metabolic enzymes found no passage addressing those claims. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • There is accumulating evidence of altered brain cholesterol metabolism in RTT.

    “as well as by accumulating evidence of altered brain cholesterol metabolism in RTT (Ben-Shachar et al., 2009;Buchovecky et al., 2013b;Lopez et al., 2017;Lütjohann et al., 2018;Urdinguio et al., 2008;Villani et al., 2016;Zandl-Lang et al., 2022).”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Ben-Shachar et al., 2009

    The Results describe altered gene expression in the cerebellum and hypothalamus of MeCP2-disorder mouse models, including a change involving a low-density-lipoprotein-related receptor. They do not say that brain cholesterol metabolism is altered in RTT. Searches for cholesterol, lipid metabolism, and sterol biosynthesis found no passage addressing that point. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Authors
Ben-Shachar, S., Chahrour, M., Thaller, C., Shaw, C. A., & Zoghbi, H. Y.
Affiliations
Howard Hughes Medical Institute (US)
Corresponding author
Zoghbi, Huda Y.
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2009-04-15
Volume
18
Issue
13
Pages
2431-2442
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddp181
PMC
PMC2694691
OpenAlex
W2146258577
Cited by
253
References
5
Citations by year
2026: 9 · 2025: 10 · 2024: 10 · 2023: 7 · 2022: 16 · 2021: 17 · 2020: 7 · 2019: 16 · 2018: 21 · 2017: 20 · 2016: 25 · 2015: 14 · 2014: 23 · 2013: 19 · 2012: 16
FWCI
7.60
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • Simons Foundation
  • International Rett Syndrome Foundation
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (NS057819, R01NS057819)
  • National Institute of Child Health and Human Development (HD024064)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 024064, P30HD024064)
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 › Genetic Neurodegenerative Diseases
Keywords
Rett syndrome, MECP2 duplication syndrome, MeCP2, cerebellum, hypothalamus, gene expression changes, transcriptional repression, transcriptional activation, Mecp2-null mice, neurodevelopmental disorders, mouse model
MeSH terms
Animals, Cerebellum, Disease Models, Animal, Gene Expression Regulation, Humans, Hypothalamus, Mice, Inbred C57BL, Mice, Transgenic, Rett Syndrome, Mice, Knockout, Gene Dosage, Mice, Methyl-CpG-Binding Protein 2

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