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Cited by 12Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Identification of Region-Specific Cytoskeletal and Molecular Alterations in Astrocytes of Mecp2 Deficient Animals

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Albizzati, Elena, Florio, Elena, Miramondi, Federica, Sormonta, Irene, Landsberger, Nicoletta, Frasca, Angelisa·2022·Frontiers in Neuroscience
DOI 10.3389/fnins.2022.823060PMC PMC8886113
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Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder that represents the most common genetic cause of severe intellectual disability in females. Most patients carry mutations in the X-linked MECP2 gene, coding for the methyl-CpG-binding protein 2 (MeCP2), originally isolated as an epigenetic transcriptional factor able to bind methylated DNA and repress transcription. Recent data implicated a role for glia in RTT, showing that astrocytes express Mecp2 and that its deficiency affects their ability to support neuronal maturation by non-cell autonomous mechanisms. To date, some molecular, structural and functional alterations have been attributed to Mecp2 null astrocytes, but how they evolve over time and whether they follow a spatial heterogeneity are two aspects which deserve further investigations. In this study, we assessed cytoskeletal features of astrocytes in Mecp2 deficient brains by analyzing their arbor complexity and processes in reconstructed GFAP + cells at different ages, corresponding to peculiar stages of the disorder, and in different cerebral regions (motor and somatosensory cortices and CA1 layer of hippocampus). Our findings demonstrate the presence of defects in Mecp2 null astrocytes that worsen along disease progression and strictly depend on the brain area, highlighting motor and somatosensory cortices as the most affected regions. Of relevance, astrocyte cytoskeleton is impaired also in the somatosensory cortex of symptomatic heterozygous animals, with Mecp2 + astrocytes showing slightly more pronounced defects with respect to the Mecp2 null cells, emphasizing the importance of non-cell autonomous effects. We reported a temporal correlation between the progressive thinning of layer I and the atrophy of astrocytes, suggesting that their cytoskeletal dysfunctions might contribute to cortical defects. Considering the reciprocal link between morphology and function in astrocytes, we analyzed the effect of Mecp2 deficiency on the expression of selected astrocyte-enriched genes, which describe typical astrocytic features. qRT-PCR data corroborated our results, reporting an overall decrement of gene expression, which is area and age-dependent. In conclusion, our data show that Mecp2 deficiency causes structural and molecular alterations in astrocytes, which progress along with the severity of symptoms and diversely occur in the different cerebral regions, highlighting the importance of considering heterogeneity when studying astrocytes in RTT.

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Authors
Albizzati, E., Florio, E., Miramondi, F., Sormonta, I., Landsberger, N., & Frasca, A.
Affiliations
  • University of Milan (IT)
  • IRCCS Ospedale San Raffaele (IT)
Corresponding author
Frasca, Angelisa
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2022-02-15
Volume
16
Pages
823060-823060
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2022.823060
PMC
PMC8886113
OpenAlex
W4225999907
Cited by
12
References
79
Citations by year
2026: 2 · 2025: 2 · 2024: 7 · 2023: 1
FWCI
1.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Università degli Studi di Milano
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 › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Rett syndrome, MeCP2, MeCP2 deficiency, astrocytes, astrocyte morphology, non-cell-autonomous effects, somatosensory cortex, motor cortex, hippocampal CA1, cortical atrophy, disease progression

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