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DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome
Open accessAbstract
Down syndrome (DS), caused by trisomy of chromosome 21, occurs in 1 of every 800 live births. Early defects in cortical development likely account for the cognitive impairments in DS, although the underlying molecular mechanism remains elusive. Here, we performed histological assays and unbiased single-cell RNA-Seq (scRNA-Seq) analysis on cerebral organoids derived from 4 euploid cell lines and from induced pluripotent stem cells (iPSCs) from 3 individuals with trisomy 21 to explore cell-type-specific abnormalities associated with DS during early brain development. We found that neurogenesis was significantly affected, given the diminished proliferation and decreased expression of layer II and IV markers in cortical neurons in the subcortical regions; this may have been responsible for the reduced size of the organoids. Furthermore, suppression of the DSCAM/PAK1 pathway, which showed enhanced activity in DS, using CRISPR/Cas9, CRISPR interference (CRISPRi), or small-molecule inhibitor treatment reversed abnormal neurogenesis, thereby increasing the size of organoids derived from DS iPSCs. Our study demonstrates that 3D cortical organoids developed in vitro are a valuable model of DS and provide a direct link between dysregulation of the DSCAM/PAK1 pathway and developmental brain defects in DS.
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“However, results from these studies are discordant: the generation of neurons from iPSCs has been reported in some studies to be impaired74,77–79 and in others not to be impaired75,80,81, which may be explained by technical differences in the cell lines and protocols used (see Box 1).”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [77]
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“Genome-wide dysregulation of gene expression (Box 3) in neurons likely leads to over-expression and/or under-expression of key genes that regulate synaptogenesis, but specific candidates have yet to be identified74,77,81,143.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [77]
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“Analyses of NPCs arising from T21 iPSCs have provided conflicting data, with some suggesting that apoptosis is increased74,79,95 and others seeing no effect75,77,81,96.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [77]
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Metadata
- Authors
- Tang, X.-Y., Xu, L., Wang, J., Hong, Y., Wang, Y., Zhu, Q., Wang, D., Zhang, X.-Y., Liu, C.-Y., Fang, K.-H., Han, X., Wang, S., Wang, X., Xu, M., Bhattacharyya, A., Guo, X., Lin, M., & Liu, Y.
- Affiliations
- State Key Laboratory of Reproductive Medicine (CN)
- Nanjing Medical University (CN)
- Xiamen University (CN)
- University of Wisconsin–Madison (US)
- Corresponding author
- Guo, Xing
- Lin, Mingyan
- Liu, Yan
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2021-06-15
- Volume
- 131
- Issue
- 12
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC8203468
- OpenAlex
- W3158718113
- Cited by
- 143
- References
- 64
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 28 · 2023: 34 · 2022: 30 · 2021: 6
- FWCI
- 21.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Chinese Academy of Sciences (XDA16010306)
- Government of Jiangsu Province
- National Key Research and Development Program of China (2019YFA0802703)
- 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
- Down syndrome, Dscam, PAK1, neurogenesis, brain organoids, iPSC-derived organoids, cortical development, CRISPR interference, small molecule inhibitors, cognitive impairment, in vitro disease model
- MeSH terms
- Cell Line, Cerebral Cortex, Down Syndrome, Humans, Organoids, Signal Transduction, Cell Adhesion Molecules, p21-Activated Kinases, Neurogenesis, Induced Pluripotent Stem Cells
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