OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome
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Abstract
Down syndrome (DS) is a common neurodevelopmental disorder, and cognitive defects in DS patients may arise from imbalances in excitatory and inhibitory neurotransmission. Understanding the mechanisms underlying such imbalances may provide opportunities for therapeutic intervention. Here, we show that human induced pluripotent stem cells (hiPSCs) derived from DS patients overproduce OLIG2+ ventral forebrain neural progenitors. As a result, DS hiPSC-derived cerebral organoids excessively produce specific subclasses of GABAergic interneurons and cause impaired recognition memory in neuronal chimeric mice. Increased OLIG2 expression in DS cells directly upregulates interneuron lineage-determining transcription factors. shRNA-mediated knockdown of OLIG2 largely reverses abnormal gene expression in early-stage DS neural progenitors, reduces interneuron production in DS organoids and chimeric mouse brains, and improves behavioral deficits in DS chimeric mice. Thus, altered OLIG2 expression may underlie neurodevelopmental abnormalities and cognitive defects in DS patients.
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A few studies indicate that increased proportions of OLIG2-expressing progenitor cells are produced by trisomy 21 induced pluripotent stem cells differentiated in both two-dimensional and three-dimensional cultures, compared to controls.
“Nonetheless, a few studies indicate that increased proportions of OLIG2-expressing progenitor cells are produced by T21 iPSCs differentiated in both two-dimensional and three-dimensional cultures, compared to controls73,91.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [91]
In Results, “Abnormal OLIG2 Protein Expression in DS hiPSC-Derived Ventral Forebrain Organoids” (page unavailable), the paper reports a higher proportion of OLIG2+ cells in trisomy 21 organoids than in controls. Its 2D-culture experiment, described in “Human PSC-Derived OLIG2+ Ventral Forebrain NPCs Give Rise to GABAergic Neurons” (page unavailable), examines differentiation of OLIG2+ cells but does not report a trisomy 21-versus-control comparison in 2D cultures. (LLM, conf=0.87)
Experimental — accuracy not yet measuredTrisomy 21 iPSCs overproduce OLIG2+ ventral forebrain neural progenitors and GABAergic neurons in organoids and in chimeric mouse brains.
“This study shows that trisomy 21 iPSCs overproduce OLIG2+ ventral forebrain neural progenitors and GABAergic neurons in organoids and in chimeric mouse brains.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [91]
The Results report more OLIG2+ cells in Down syndrome organoids than in controls and overproduction of GABAergic neurons in chimeric mouse brains; the organoid rescue experiments also support GABAergic-neuron overproduction. But the Results on six-month-old chimeric brains say no nestin+ human neural progenitors were found there and identify the OLIG2+ donor-derived cells as likely oligodendroglial progenitors. Thus the claim is not supported if it attributes overproduction of OLIG2+ ventral forebrain neural progenitors to the mouse brains as well as the organoids (page unavailable in our copy). (LLM, conf=0.86)
Experimental — accuracy not yet measuredEvidence from induced pluripotent stem cells differentiated to ventral forebrain-like interneuron progenitors indicates that the number of progenitors produced is different in the presence of trisomy 21.
“Evidence from iPSCs differentiated to ventral forebrain-like interneuron progenitors indicates that the number of progenitors that are produced is different in the presence of T21 (84,90,91).”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [91]
OLIG2 expression is not specific to oligodendrocyte progenitor cells and its increased expression has been shown to regulate interneuron production in organoids and chimeric mice.
“However, OLIG2 expression is not specific to oligodendrocyte progenitor cells and its increased expression has been shown to regulate interneuron production in organoids and chimeric mice91.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [91]
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“Similar to studies in Ts65Dn, a significant increase in GABAergic interneurons was identified in both isogenic and matched lines of trisomic organoids differentiated to a ventral forebrain fate (Xu et al., 2019).”
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- Authors
- Xu, R., Brawner, A. T., Li, S., Liu, J.-J., Kim, H., Xue, H., Pang, Z. P., Kim, W.-Y., Hart, R. P., Liu, Y., & Jiang, P.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- University of Nebraska Medical Center (US)
- The University of Texas Health Science Center at Houston (US)
- Kent State University (US)
- Corresponding author
- Jiang, Peng
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 24
- Issue
- 6
- Pages
- 908-926.e8
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC6944064
- OpenAlex
- W2945934042
- Cited by
- 193
- References
- 127
- Citations by year
- 2026: 15 · 2025: 31 · 2024: 24 · 2023: 23 · 2022: 38 · 2021: 34 · 2020: 20 · 2019: 8
- FWCI
- 22.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- Olig2, Down syndrome, brain organoids, iPSC-derived neurons, GABAergic interneurons, neural progenitor cells, recognition memory, cognitive impairment, neurodevelopmental abnormalities, transcription factors
- MeSH terms
- Oligodendrocyte Transcription Factor 2, Animals, Cell Differentiation, Cells, Cultured, Disease Models, Animal, Down Syndrome, Humans, Interneurons, Mice, Inbred C57BL, Organoids, Phenotype, Prosencephalon, Transplantation Chimera, Cell Lineage, RNA, Small Interfering, Mice, Neurogenesis, Induced Pluripotent Stem Cells, Neural Stem Cells, Neurodevelopmental Disorders
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