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Cited by 37Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchNeurogenesis and neuroplasticity mechanisms

Mutations in the transcriptional regulator MeCP2 severely impact key cellular and molecular signatures of human astrocytes during maturation

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Sun, Jialin, Osenberg, Sivan, Irwin, Austin, Ma, Li-Hua, Lee, Nigel, Xiang, Yangfei, Li, Feng, Wan, Ying-Wooi +3 more·2023·Cell Reports
DOI 10.1016/j.celrep.2022.111942PMC PMC10857774
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Abstract

Mutations in the MECP2 gene underlie a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT). We ask whether MECP2 mutations interfere with human astrocyte developmental maturation, thereby affecting their ability to support neurons. Using human-based models, we show that RTT-causing MECP2 mutations greatly impact the key role of astrocytes in regulating overall brain bioenergetics and that these metabolic aberrations are likely mediated by dysfunctional mitochondria. During post-natal maturation, astrocytes rely on neurons to induce their complex stellate morphology and transcriptional changes. While MECP2 mutations cause cell-intrinsic aberrations in the astrocyte transcriptional landscape, surprisingly, they do not affect the neuron-induced astrocyte gene expression. Notably, however, astrocytes are unable to develop complex mature morphology due to cell- and non-cell-autonomous aberrations caused by MECP2 mutations. Thus, MECP2 mutations critically impact key cellular and molecular features of human astrocytes and, hence, their ability to interact and support the structural and functional maturation of neurons.

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  • RTT astrocytes have a defective capacity to support synaptogenesis and synaptic functionality.

    “Considering the defective capacity of RTT astrocytes to support synaptogenesis and synaptic functionality (Albizzati et al., 2024;Sun et al., 2023), we characterized cholesterol metabolism in Mecp2 deficient astrocytes.”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Sun et al., 2023

    The Results report that mutant astrocytes were less effective than wild-type astrocytes at promoting synapse formation in neuron co-cultures. The Discussion also reports impaired glutamate uptake, a function relevant to synaptic signaling, but the paper does not directly show that mutant astrocytes impair synaptic functionality. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Mecp2 KO astrocytes influence both synaptogenesis and synapse maintenance through release of synaptotoxic molecules and/or reduced secretion of synaptogenic factors.

    “Indeed, through the release of synaptotoxic molecules and/or the reduced secretion of synaptogenic factors, Mecp2 KO astrocytes influence both synaptogenesis and synapse maintenance (Albizzati et al., 2024;Sun et al., 2023).”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Sun et al., 2023

    The Results section on astrocyte-dependent neuronal structural plasticity (page unavailable) reports that MECP2-mutant astrocytes enhanced synapse formation less efficiently than wild-type astrocytes. It does not establish an effect on synapse maintenance or show that synaptotoxic release or reduced secretion of synaptogenic factors caused the difference. The study describes MECP2-mutant human astrocytes, not specifically Mecp2-knockout astrocytes. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • MECP2 mutant astrocytes contribute to neuronal alterations through non-cell-autonomous mechanisms.

    “and MECP2 mutant astrocytes contribute to neuronal alterations through non-cell-autonomous mechanisms (Albizzati et al., 2024;Ballas et al., 2009;Sun et al., 2023;Williams et al., 2014).”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Sun et al., 2023

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Cited by

Sorted by citations

Authors
Sun, J., Osenberg, S., Irwin, A., Ma, L.-H., Lee, N., Xiang, Y., Li, F., Wan, Y.-W., Park, I.-H., Maletic-Savatic, M., & Ballas, N.
Affiliations
  • Stony Brook University (US)
  • Baylor College of Medicine (US)
  • Yale University (US)
Corresponding author
Ballas, Nurit
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2023-01
Volume
42
Issue
1
Pages
111942
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2022.111942
PMC
PMC10857774
OpenAlex
W4313498852
Cited by
37
References
11
Citations by year
2026: 6 · 2025: 11 · 2024: 17 · 2023: 3
FWCI
6.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Cancer Prevention and Research Institute of Texas
  • Rett Syndrome Research Trust
  • University of Maryland, Baltimore
  • National Institute of Mental Health
  • National Institutes of Health (R01DK121970, P30CA125123, P50HD103555, R01GM120033, R01HD081037, R21MH126381)
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 › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
MECP2 mutations, Rett syndrome, astrocyte maturation, astrocyte-neuron interaction, astrocyte morphology, brain bioenergetics, mitochondrial dysfunction, neurodevelopmental disorders, human astrocytes
MeSH terms
Astrocytes, Brain, Humans, Mutation, Neurons, Rett Syndrome, Methyl-CpG-Binding Protein 2

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