Cited by 22Genetics and Neurodevelopmental DisordersNeurogenesis and neuroplasticity mechanismsFetal and Pediatric Neurological Disorders

Tissue Plasminogen Activator Contributes to Alterations of Neuronal Migration and Activity-Dependent Responses in Fragile X Mice

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Achuta, V. Swaroop, Rezov, Veronika, Uutela, Marko, Louhivuori, Verna, Louhivuori, Lauri, Castrén, Maija L.·2014·The Journal of Neuroscience

Abstract

Fragile X syndrome (FXS) is the most common inherited neurodevelopmental disorder with intellectual disability. Here, we show that the expression of tissue plasminogen activator (tPA) is increased in glial cells differentiated from neural progenitors of Fmr1 knock-out mice, a mouse model for FXS, and that tPA is involved in the altered migration and differentiation of these progenitors lacking FMR1 protein (FMRP). When tPA function is blocked with an antibody, enhanced migration of doublecortin-immunoreactive neurons in 1 d differentiated FMRP-deficient neurospheres is normalized. In time-lapse imaging, blocking the tPA function promotes early glial differentiation and reduces the velocity of nuclear movement of FMRP-deficient radial glia. In addition, we show that enhanced intracellular Ca 2+responses to depolarization with potassium are prevented by the treatment with the tPA-neutralizing antibody in FMRP-deficient cells during early neural progenitor differentiation. Alterations of the tPA expression in the embryonic, postnatal, and adult brain of Fmr1 knock-out mice suggest an important role for tPA in the abnormal neuronal differentiation and plasticity in FXS. Altogether, the results indicate that tPA may prove to be an interesting potential target for pharmacological intervention in FXS.

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Crossref · 10.1523/jneurosci.3753-13.2014

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  • IBA-1 and GFAP are well-established markers of immune stimulation.

    “To evaluate the impact of Di-siRNA injection on microglia activation and gliosis, we measured two well-established markers of immune stimulation, IBA-1 and GFAP.”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [30]

    The section on increased tPA expression identifies GFAP as an astrocytic marker, supporting its use to identify glial cells. Our copy does not identify GFAP as a marker of immune stimulation or discuss IBA-1; the claimed role of both markers in assessing immune stimulation is therefore not established by this source. No page number is available in the indexed copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured
  • GFAP is an intermediate filament protein and increases as a result of astrocyte proliferation.

    “GFAP is an intermediate filament protein and increases as a result of astrocyte proliferation30.”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [30]

    The Materials and Methods section identifies GFAP as glial fibrillary acidic protein, and the section on increased tPA expression calls it an astrocytic marker. The paper does not describe GFAP as an intermediate filament protein or say that GFAP increases because of astrocyte proliferation; the reported increase is in tPA, not GFAP. No page numbers are available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured
  • tPA is increased in cortical supragranular layers I-III but decreased in layers IV-V at P7 in the Fmr1 KO brain.

    “Colocalising with GFAP, tPA is increased in cortical supragranular layers I-III but decreased in layers IV-V at P7 in the Fmr1 KO brain (Achuta et al., 2014).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Achuta et al., 2014

    The section on altered tPA expression in developing Fmr1 KO mice (Fig. 4C,D; page unavailable) reports more tPA-positive cells in cortical layers I–III and fewer in layers IV–V at P7. The paper reports tPA colocalization with GFAP in differentiated progenitors and adult cortex, but does not establish that colocalization for the P7 cortical-layer finding. (LLM, conf=0.86)

    Experimental — accuracy not yet measured
  • Expression of tissue plasminogen activator (tPA) is increased in differentiating Fmr1 KO neural progenitors, indicating increased tPA activity.

    “Expression of tissue plasminogen activator (tPA) is increased in differentiating Fmr1 KO neural progenitors, indicating increased tPA activity (Achuta et al., 2014).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Achuta et al., 2014

    The section on increased tPA expression in neural progenitor cells (page unavailable) reports more tPA-immunoreactive cells after differentiation of Fmr1 KO progenitors than wild-type controls. It does not establish that tPA enzymatic activity increased; the claim’s activity inference goes beyond the reported expression finding. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • Augmented intracellular Ca2+ responses to membrane depolarization with high extracellular K+ are dependent on tPA in Fmr1 KO mouse NPCs.

    “Augmented intracellular Ca2+ responses to membrane depolarization with high extracellular K+ are dependent on tPA in Fmr1 KO mouse NPCs (Achuta et al., 2014).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Achuta et al., 2014

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Authors
Achuta, V. S., Rezov, V., Uutela, M., Louhivuori, V., Louhivuori, L., & Castrén, M. L.
Affiliations
University of Helsinki (FI)
Venue
The Journal of Neuroscience
Published
2014-01-29
Volume
34
Issue
5
Pages
1916-1923
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2035501419
Cited by
22
References
54
Citations by year
2025: 1 · 2024: 1 · 2022: 1 · 2021: 2 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 1
FWCI
1.97
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
Keywords
tissue plasminogen activator, fragile X syndrome, FMRP, Fmr1 knockout mice, neural progenitor differentiation, neuronal migration, radial glia, glial differentiation, calcium signaling, neurospheres, doublecortin, neurodevelopmental disorders, therapeutic target
MeSH terms
Fatty Acid-Binding Protein 7, Doublecortin Domain Proteins, Animals, Animals, Newborn, Calcium, Cell Movement, Cells, Cultured, Disease Models, Animal, Embryo, Mammalian, Female, Fibrinolytic Agents, Fragile X Syndrome, Glial Fibrillary Acidic Protein, Humans, Male, Mice, Inbred C57BL, Microtubule-Associated Proteins, Nerve Tissue Proteins, Neurons, Neuropeptides, Tissue Plasminogen Activator, Pregnancy, Plasminogen Activator Inhibitor 1, Mice, Knockout, Gene Expression Regulation, Developmental, Fatty Acid-Binding Proteins, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Neural Stem Cells

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