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Cited by 13Down syndrome and intellectual disability researchPluripotent Stem Cells ResearchGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction

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Bansal, Prakhar, Banda, Erin C., Glatt-Deeley, Heather R., Stoddard, Christopher E., Linsley, Jeremy W., Arora, Neha, Deleschaux, Cécile, Ahern, Darcy T. +8 more·2024·Science Advances
DOI 10.1126/sciadv.adj0385PMC PMC11160455

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Abstract

Excess gene dosage from chromosome 21 (chr21) causes Down syndrome (DS), spanning developmental and acute phenotypes in terminal cell types. Which phenotypes remain amenable to intervention after development is unknown. To address this question in a model of DS neurogenesis, we derived trisomy 21 (T21) human induced pluripotent stem cells (iPSCs) alongside, otherwise, isogenic euploid controls from mosaic DS fibroblasts and equipped one chr21 copy with an inducible XIST transgene. Monoallelic chr21 silencing by XIST is near-complete and irreversible in iPSCs. Differential expression reveals that T21 neural lineages and iPSCs share suppressed translation and mitochondrial pathways and activate cellular stress responses. When XIST is induced before the neural progenitor stage, T21 dosage correction suppresses a pronounced skew toward astrogenesis in neural differentiation. Because our transgene remains inducible in postmitotic T21 neurons and astrocytes, we demonstrate that XIST efficiently represses genes even after terminal differentiation, which will empower exploration of cell type–specific T21 phenotypes that remain responsive to chr21 dosage.

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  • Increased astrogliogenesis can be partially reversed by silencing HSA21 by the non-coding RNA XIST in induced pluripotent stem cell-derived astrocyte progenitor cells.

    “This increased astrogliogenesis can be partially reversed by the silencing of HSA21 by the non-coding RNA XIST in iPSC-derived astrocyte progenitor cells104,105.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [105]

    The Results section ('T21 dosage correction early in neural differentiation rescues neurogenesis') reports that XIST-mediated trisomy 21 silencing suppresses the excess astrocyte lineage commitment, supporting the reversal claim. But the correction was initiated in iPSCs or on the first day of differentiation, before the neural progenitor cell stage; the paper does not identify the treated cells as astrocyte progenitor cells. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Bansal, P., Banda, E. C., Glatt-Deeley, H. R., Stoddard, C. E., Linsley, J. W., Arora, N., Deleschaux, C., Ahern, D. T., Kondaveeti, Y., Massey, R. E., Nicouleau, M., Wang, S., Sabariego-Navarro, M., Dierssen, M., Finkbeiner, S., & Pinter, S. F.
Affiliations
  • University of Connecticut (US)
  • UConn Health (US)
  • Gladstone Institutes (US)
  • Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA.
  • Barcelona Institute of Science and Technology (ES)
  • Universitat Pompeu Fabra (ES)
Corresponding author
  • Bansal, Prakhar
  • Banda, Erin C.
  • Pinter, Stefan F.
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-06-07
Volume
10
Issue
23
Pages
eadj0385-eadj0385
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.adj0385
PMC
PMC11160455
OpenAlex
W4399425562
Cited by
13
References
16
Citations by year
2026: 9 · 2025: 2 · 2024: 2
FWCI
5.38
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by-nc-nd)
Funders
  • University of Connecticut (R35GM124926)
  • National Institutes of Health
  • National Institute on Aging (R01AG064579)
  • National Heart, Lung, and Blood Institute (R01HL141324)
  • National Institute of General Medical Sciences (R35GM124926)
  • National Institute of Neurological Disorders and Stroke (RF1NS128800)
  • U.S. National Library of Medicine (R01LM013617)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
Down syndrome, XIST, induced pluripotent stem cells, neuronal differentiation, neurogenesis, astrocyte differentiation, neural progenitor cells, protein synthesis inhibition, mitochondrial pathway, cellular stress response, in vitro disease model
MeSH terms
Cell Differentiation, Chromosomes, Human, Pair 21, Down Syndrome, Humans, Neurons, Gene Dosage, Neurogenesis, Induced Pluripotent Stem Cells, RNA, Long Noncoding

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