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Cited by 86Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchNeurogenesis and neuroplasticity mechanisms

Aberrant astrocyte protein secretion contributes to altered neuronal development in multiple models of neurodevelopmental disorders.

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Caldwell, Alison L. M., Sancho, Laura, Deng, James, Bosworth, Alexandra, Miglietta, Audrey, Diedrich, Jolene K., Shokhirev, Maxim N., Allen, Nicola J.·2022·Nature Neuroscience
DOI 10.1038/s41593-022-01150-1PMC PMC10395413

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Abstract

Astrocytes negatively impact neuronal development in many models of neurodevelopmental disorders (NDs); however, how they do this, and if mechanisms are shared across disorders, is not known. In this study, we developed a cell culture system to ask how astrocyte protein secretion and gene expression change in three mouse models of genetic NDs (Rett, Fragile X and Down syndromes). ND astrocytes increase release of Igfbp2, a secreted inhibitor of insulin-like growth factor (IGF). IGF rescues neuronal deficits in many NDs, and we found that blocking Igfbp2 partially rescues inhibitory effects of Rett syndrome astrocytes, suggesting that increased astrocyte Igfbp2 contributes to decreased IGF signaling in NDs. We identified that increased BMP signaling is upstream of protein secretion changes, including Igfbp2, and blocking BMP signaling in Fragile X and Rett syndrome astrocytes reverses inhibitory effects on neurite outgrowth. This work provides a resource of astrocyte-secreted proteins in health and ND models and identifies novel targets for intervention in diverse NDs.

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  • DS alters the secretome of astrocytes, which exerts a direct impact on synaptogenesis.

    “For example, DS has been shown to alter the secretome (the factors secreted by cells) of astrocytes, which exerts a direct impact on synaptogenesis131,144.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [144]

  • Absence of FMRP appears to influence the dynamics of astrocyte maturation, and some mechanisms may be shared with other neurodevelopmental disorders.

    “Absence of FMRP appears to influence the dynamics of astrocyte maturation, and some of the mechanisms may be shared with other neurodevelopmental disorders (Caldwell et al., 2022).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Caldwell et al., 2022

  • Phospho-SMAD positive astrocytes are increased in Fmr1 KO cortex at P7, indicating increased BMP activity.

    “Phospho-SMAD positive astrocytes are increased in Fmr1 KO cortex at P7, indicating increased bone morphogenetic protein (BMP) activity.”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Caldwell et al., 2022

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References 97 · Cited by 86

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Authors
Caldwell, A. L. M., Sancho, L., Deng, J., Bosworth, A., Miglietta, A., Diedrich, J. K., Shokhirev, M. N., & Allen, N. J.
Affiliations
Salk Institute for Biological Studies (US)
Corresponding author
Allen, Nicola J.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2022-08-30
Volume
25
Issue
9
Pages
1163-1178
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-022-01150-1
PMC
PMC10395413
OpenAlex
W4293582032
Cited by
86
References
97
Citations by year
2026: 15 · 2025: 27 · 2024: 25 · 2023: 15 · 2022: 3 · 2021: 1
FWCI
10.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Mary K. Chapman Foundation
  • Autism Speaks (10640)
  • U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (F30 HD106699)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (NIH-NCI CCSG: P30 014195)
  • Leona M. and Harry B. Helmsley Charitable Trust
  • Hearst Foundations
  • Pew Charitable Trusts
  • Chan Zuckerberg Initiative Salk Institute Innovation Grant
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
neurodevelopmental disorders, Rett syndrome, fragile X syndrome, Down syndrome, IGFBP-2, insulin-like growth factor signaling, BMP signaling, neurite outgrowth, astrocyte-neuron interaction, mouse model
MeSH terms
Animals, Astrocytes, Neurons, Rett Syndrome, Mice, Neurogenesis, Neurodevelopmental Disorders

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