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Cited by 16Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

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Peteri, Ulla‐Kaisa, Pitkonen, Juho, de Toma, Ilario, Nieminen, Otso, Utami, Kagistia Hana, Strandin, Tomas M., Corcoran, Padraic, Roybon, Laurent +5 more·2021·Glia
DOI 10.1002/glia.24080
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Abstract

The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell‐derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes. Levels of uPA were also increased in conditioned medium collected from FXS hiPSC‐derived astrocyte cultures and correlated inversely with intracellular Ca 2+ responses to activation of L‐type voltage‐gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB within the docking site for the phospholipase‐Cγ1 (PLCγ1), indicating effects of uPA on neuronal plasticity. Gene expression changes during neuronal differentiation preceding astrogenesis likely contributed to properties of astrocytes with FXS‐specific alterations that showed specificity by not affecting differentiation of adenosine triphosphate (ATP)‐responsive astrocyte population. To conclude, our studies identified uPA as an important regulator of astrocyte function and demonstrated that increased uPA in human FXS astrocytes modulated astrocytic responses and neuronal plasticity.

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  • Immature human FXS astrocytes secrete uPA more than healthy control astrocytes, and increased uPA augments TrkB phosphorylation within the docking site for PLCγ1 in cocultured rat primary neurons.

    “These immature human FXS astrocytes also secrete uPA more than healthy control astrocytes, and the increased uPA augments tyrosine receptor kinase B (TrkB) phosphorylation within the docking site for phospholipase-Cγ1 (PLCγ1) in cocultured rat primary neurons (Peteri et al., 2021).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Peteri et al., 2021

    Section 3.4 reports 5.5-fold higher uPA in medium from human FXS astrocytes than controls. Section 3.6 reports increased phosphorylation of the PLCγ1-binding TrkB site in rat primary cortical neurons exposed to that medium, with the increase prevented by a uPA antibody. The neurons were treated with astrocyte-conditioned medium, not cocultured with the astrocytes as the claim states. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In human FXS iPSC-derived astrocytes, L-type calcium channel-dependent Ca2+ responses to high extracellular K+ were reduced compared with controls and showed strong inverse correlation with ACM uPA levels, demonstrating that altered Ca2+ signaling in FXS astrocytes modulates neuronal plasticity.

    “In human FXS iPSC-derived astrocytes, L-type calcium channel-dependent Ca2+ responses to high extracellular K+ were reduced when compared with controls and these responses showed strong inverse correlation with ACM uPA levels (Peteri et al., 2021), demonstrating that altered Ca2+ signaling in FXS astrocytes modulates neuronal plasticity.”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Peteri et al., 2021

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • uPA is increased in FXS hiPSC-derived forebrain astrocytes.

    “uPA is increased in FXS hiPSC-derived forebrain astrocytes (Peteri et al., 2021).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Peteri et al., 2021

  • Orphan receptor GPR124 is differently expressed in FXS and control astrocytes and may represent a partner receptor that acts through WNT/β-catenin signaling, which is altered in FXS models.

    “Orphan receptor GPR124 (Chen et al., 2019) is differently expressed in FXS and control astrocytes and may represent a partner receptor that acts through WNT/β-catenin signaling, which is altered in FXS models (Peteri et al., 2021).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Peteri et al., 2021

  • hESC-derived FMR1 KO astrocytes expressed less ABCA1 than their isogenic controls (log2 −6.41-fold change, P = 0.0004, P adjust = 0.125) in RNA-Seq analysis.

    “Similarly, human embryonic stem cell (hESC)-derived FMR1 KO astrocytes expressed less ABCA1 than their isogenic controls (log2 −6.41-fold change, P = 0.0004, P adjust = 0.125) in RNA-Seq analysis26.”

    From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [26]

    Sections 2.3 and 3.2 describe RNA-seq comparing isogenic FMR1-knockout and control astrocytes. However, the passages retrieved by searching for ABCA1 and the reported values do not identify an ABCA1 result or verify its fold change and P values; the claim cannot be checked against our copy. (LLM, conf=0.72)

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Authors
Peteri, U., Pitkonen, J., de Toma, I., Nieminen, O., Utami, K. H., Strandin, T. M., Corcoran, P., Roybon, L., Vaheri, A., Ethell, I., Casarotto, P., Pouladi, M. A., & Castrén, M. L.
Affiliations
  • University of Helsinki (FI)
  • Systems Neurobiology Laboratory Barcelona Institute of Science and Technology Barcelona Spain
  • National University of Singapore (SG)
  • Array and Analysis Facility, Department of Medical Sciences Uppsala University Uppsala Sweden
  • Lund University (SE)
  • University of California, Riverside (US)
  • University of British Columbia (CA)
Corresponding author
Castrén, Maija L.
ORCID
Venue
Glia
Publisher
Wiley
Published
2021-08-24
Volume
69
Issue
12
Pages
2947-2962
ISSN
  • 0894-1491 (ISSN-L)
  • 1098-1136
DOI
10.1002/glia.24080
OpenAlex
W3194498969
Cited by
16
References
3
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 1
FWCI
1.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Glia (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • FRAXA Research Foundation
  • Lastentautien Tutkimussäätiö
  • Michael Smith Foundation for Health Research
  • Academy of Finland
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
urokinase, fragile X syndrome, astrocytes, extracellular matrix degradation, induced pluripotent stem cells, L-type calcium channels, intracellular calcium, TrkB phosphorylation, PLCγ1, neuroplasticity, intellectual disability, autism spectrum disorder, astrocyte differentiation
MeSH terms
Autism Spectrum Disorder, Animals, Astrocytes, Fragile X Syndrome, Humans, Urokinase-Type Plasminogen Activator, Mice, Induced Pluripotent Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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