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Cited by 54Genetics and Neurodevelopmental DisordersNeurogenesis and neuroplasticity mechanismsRNA and protein synthesis mechanisms

Cell-type-specific profiling of human cellular models of fragile X syndrome reveal PI3K-dependent defects in translation and neurogenesis.

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Raj, Nisha, McEachin, Zachary T., Harousseau, William, Zhou, Ying, Zhang, Feiran, Merritt-Garza, Megan E., Taliaferro, J. Matthew, Kalinowska, Magdalena +12 more·2021·Cell Reports
DOI 10.1016/j.celrep.2021.108991PMC PMC8133829
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Abstract

Transcriptional silencing of the FMR1 gene in fragile X syndrome (FXS) leads to the loss of the RNA-binding protein FMRP. In addition to regulating mRNA translation and protein synthesis, emerging evidence suggests that FMRP acts to coordinate proliferation and differentiation during early neural development. However, whether loss of FMRP-mediated translational control is related to impaired cell fate specification in the developing human brain remains unknown. Here, we use human patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells and organoids to model neurogenesis in FXS. We developed a high-throughput, in vitro assay that allows for the simultaneous quantification of protein synthesis and proliferation within defined neural subpopulations. We demonstrate that abnormal protein synthesis in FXS is coupled to altered cellular decisions to favor proliferative over neurogenic cell fates during early development. Furthermore, pharmacologic inhibition of elevated phosphoinositide 3-kinase (PI3K) signaling corrects both excess protein synthesis and cell proliferation in a subset of patient neural cells.

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  • Delayed cell cycle progression and extended maintenance of immature proliferating neural progenitor cells are found in both human and mouse FXS models.

    “Delayed cell cycle progression and extended maintenance of immature proliferating neural progenitor cells (NPCs) are found in both human and mouse FXS models (Edens et al., 2019; Raj et al., 2021).”

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

    The Results sections on cell fate and cell-cycle alterations report more proliferating NPCs and immature neuroblasts, fewer mature cells, and an altered distribution of human FXS NPCs across cell-cycle phases. They do not establish delayed cell-cycle progression. Raj et al. study human models; the sentence also cites Edens et al. for the broader human-and-mouse statement. Page numbers are not available in our copy. (LLM, conf=0.86)

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Authors
Raj, N., McEachin, Z. T., Harousseau, W., Zhou, Y., Zhang, F., Merritt-Garza, M. E., Taliaferro, J. M., Kalinowska, M., Marro, S. G., Hales, C. M., Berry-Kravis, E., Wolf-Ochoa, M. W., Martinez-Cerdeño, V., Wernig, M., Chen, L., Klann, E., Warren, S. T., Jin, P., Wen, Z., & Bassell, G. J.
Affiliations
  • Emory University (US)
  • University of Colorado Anschutz (US)
  • New York University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Stanford University (US)
  • Stanford Medicine (US)
Corresponding author
  • Raj, Nisha
  • Bassell, Gary J.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2021-04
Volume
35
Issue
2
Pages
108991
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2021.108991
PMC
PMC8133829
OpenAlex
W3155648953
Cited by
54
References
10
Citations by year
2026: 6 · 2025: 6 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 3
FWCI
5.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • NINDS
  • NICHD
  • Boettcher Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
fragile X syndrome, FMRP, FMR1 gene silencing, PI3K signaling, protein synthesis, translational regulation, neural progenitor cells, organoids, neurogenesis, cell proliferation, cell fate specification, iPSC-derived neural cells, high-throughput assay
MeSH terms
Phosphoinositide-3 Kinase Inhibitors, Biological Assay, Cell Differentiation, Fragile X Syndrome, Humans, Imidazoles, Models, Biological, Morpholines, Organoids, Piperazines, Pyrimidinones, RNA, Messenger, Protein Biosynthesis, Signal Transduction, Gene Expression Regulation, Developmental, Cell Lineage, Cell Proliferation, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein, Neurogenesis, Induced Pluripotent Stem Cells, Class I Phosphatidylinositol 3-Kinases, Neural Stem Cells, Primary Cell Culture

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