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Cited by 5Genetics and Neurodevelopmental DisordersPluripotent Stem Cells ResearchDown syndrome and intellectual disability research

Reduced LYNX1 expression in transcriptome of human iPSC-derived neural progenitors modeling fragile X syndrome.

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Talvio, Karo, Minkeviciene, Rimante, Townsley, Kayla G., Achuta, Venkat Swaroop, Huckins, Laura M., Corcoran, Padraic, Brennand, Kristen J., Castrén, Maija L.·2022·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2022.1034679PMC PMC9731341
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Abstract

Lack of FMR1 protein results in fragile X syndrome (FXS), which is the most common inherited intellectual disability syndrome and serves as an excellent model disease to study molecular mechanisms resulting in neuropsychiatric comorbidities. We compared the transcriptomes of human neural progenitors (NPCs) generated from patient-derived induced pluripotent stem cells (iPSCs) of three FXS and three control male donors. Altered expression of RAD51C, PPIL3, GUCY1A2, MYD88, TRAPPC4, LYNX1, and GTF2A1L in FXS NPCs suggested changes related to triplet repeat instability, RNA splicing, testes development, and pathways previously shown to be affected in FXS. LYNX1 is a cholinergic brake of tissue plasminogen activator (tPA)-dependent plasticity, and its reduced expression was consistent with augmented tPA-dependent radial glial process growth in NPCs derived from FXS iPSC lines. There was evidence of human iPSC line donor-dependent variation reflecting potentially phenotypic variation. NPCs derived from an FXS male with concomitant epilepsy expressed differently several epilepsy-related genes, including genes shown to cause the auditory epilepsy phenotype in the murine model of FXS. Functional enrichment analysis highlighted regulation of insulin-like growth factor pathway in NPCs modeling FXS with epilepsy. Our results demonstrated potential of human iPSCs in disease modeling for discovery and development of therapeutic interventions by showing early gene expression changes in FXS iPSC-derived NPCs consistent with the known pathophysiological changes in FXS and by revealing disturbed FXS progenitor growth linked to reduced expression of LYNX1, suggesting dysregulated cholinergic system.

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  • In transcriptomics analysis of human FXS NPCs, MYD88 was amongst the most significantly overexpressed genes.

    “In the transcriptomics analysis of human FXS NPCs, MYD88 was amongst the most significantly overexpressed genes (Talvio et al., 2022) and there are several tentative arguments for MYD88-mediated system overactivity in FXS astrocytes.”

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

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Authors
Talvio, K., Minkeviciene, R., Townsley, K. G., Achuta, V. S., Huckins, L. M., Corcoran, P., Brennand, K. J., & Castrén, M. L.
Affiliations
  • University of Helsinki (FI)
  • Icahn School of Medicine at Mount Sinai (US)
  • Medical University of Vienna (AT)
  • Yale University (US)
Corresponding author
Castrén, Maija L.
ORCID
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2022-11-21
Volume
10
Pages
1034679-1034679
ISSN
2296-634X (ISSN-L)
DOI
10.3389/fcell.2022.1034679
PMC
PMC9731341
OpenAlex
W4309788318
Cited by
5
References
105
Citations by year
2026: 1 · 2025: 1 · 2024: 3
FWCI
0.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • FRAXA Research Foundation
  • Lastentautien Tutkimussäätiö
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Keywords
fragile X syndrome, Lynx1, neural progenitor cells, induced pluripotent stem cells, disease modeling, transcriptome, FMR1 gene, triplet repeat instability, RNA splicing, tissue plasminogen activator, cholinergic system, epilepsy, insulin-like growth factor pathway, intellectual disability

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