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Cited by 47Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchNeuroscience and Neuropharmacology Research

Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome.

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Utami, Kagistia Hana, Skotte, Niels H., Colaço, Ana R., Yusof, Nur Amirah Binte Mohammad, Sim, Bernice, Yeo, Xin Yi, Bae, Han-Gyu, Garcia-Miralles, Marta +11 more·2020·Biological Psychiatry
DOI 10.1016/j.biopsych.2020.05.005

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Abstract

Background Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have been largely performed in rodent or nonisogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal properties in the context of isogenic human neurons remains lacking. Methods Using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to introduce indels in exon 3 of FMR1, we generated an isogenic human pluripotent stem cell model of FXS that shows complete loss of FMRP expression. We generated neuronal cultures and performed genome-wide transcriptome and proteome profiling followed by functional validation of key dysregulated processes. We further analyzed neurodevelopmental and neuronal properties, including neurite length and neuronal activity, using multielectrode arrays and patch clamp electrophysiology. Results We showed that the transcriptome and proteome profiles of isogenic FMRP-deficient neurons demonstrate perturbations in synaptic transmission, neuron differentiation, cell proliferation and ion transmembrane transporter activity pathways, and autism spectrum disorder-associated gene sets. We uncovered key deficits in FMRP-deficient cells demonstrating abnormal neural rosette formation and neural progenitor cell proliferation. We further showed that FMRP-deficient neurons exhibit a number of additional phenotypic abnormalities, including neurite outgrowth and branching deficits and impaired electrophysiological network activity. These FMRP-deficient related impairments have also been validated in additional FXS patient-derived human-induced pluripotent stem cell neural cells. Conclusions Using isogenic human pluripotent stem cells as a model to investigate the pathophysiology of FXS in human neurons, we reveal key neural abnormalities arising from the loss of FMRP.

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  • Loss of FMRP-mediated translational control results in altered cell fate specification during early neural development.

    “Loss of FMRP-mediated translational control results in altered cell fate specification during early neural development (Tervonen et al., 2009; Saffary and Xie, 2011; Utami et al., 2020).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Utami et al., 2020

    The ‘Loss of FMRP leads to abnormal neural rosette formation and increased neural progenitor proliferation’ section (p. 8) reports smaller neural rosettes and increased progenitor proliferation, supporting an effect on early neural development. It does not establish altered cell fate specification as a result of lost translational control; the ‘Transcriptome and proteome analyses’ section reports comparable neural-versus-glial cell proportions across lines. (LLM, conf=0.86)

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Cited by

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Authors
Utami, K. H., Skotte, N. H., Colaço, A. R., Yusof, N. A. B. M., Sim, B., Yeo, X. Y., Bae, H.-G., Garcia-Miralles, M., Radulescu, C. I., Chen, Q., Chaldaiopoulou, G., Liany, H., Nama, S., Peteri, U.-K. A., Sampath, P., Castrén, M. L., Jung, S., Mann, M., & Pouladi, M. A.
Affiliations
  • Agency for Science, Technology and Research (SG)
  • University of Copenhagen (DK)
  • University of Helsinki (FI)
Corresponding author
Pouladi, Mahmoud A.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2020-09
Volume
88
Issue
6
Pages
500-511
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2020.05.005
OpenAlex
W3024746958
Cited by
47
References
13
Citations by year
2026: 6 · 2025: 7 · 2024: 4 · 2023: 12 · 2022: 9 · 2021: 7 · 2020: 2
FWCI
4.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion, cc-by-nc-nd)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Weill Cornell Medical College
  • Australian Research Council
  • Agency for Science, Technology and Research
  • Novo Nordisk Fonden (NNF14CC0001, NNF15CC0001)
  • FRAXA Research Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
fragile X syndrome, FMRP, FMR1 gene, gene expression profiling, proteomic profiling, synaptic transmission, neural progenitor proliferation, neurite outgrowth, neuronal network activity, neurodevelopmental deficits
MeSH terms
Autism Spectrum Disorder, Fragile X Syndrome, Humans, Neurons, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Induced Pluripotent Stem Cells

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