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Updated: Nov 6, 2025
In Vitro Modeling of Down Syndrome Neurogenesis Using Human-Induced Pluripotent Stem Cells
Published on: March 7, 2025
DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with
Xiao-Yan Tang1, Lei Xu1, Jingshen Wang2
1Department of Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive Medicine, School of Pharmacy, and.
Abstract:
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.
Insights
Down syndrome (DS) brain development defects are linked to the DSCAM/PAK1 pathway. Inhibiting this pathway in cerebral organoids normalized neurogenesis and increased organoid size, offering therapeutic insights.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Down syndrome (DS), caused by trisomy 21, affects 1 in 800 births.
- Cognitive impairments in DS are suspected to originate from early cortical development defects.
- The precise molecular mechanisms underlying these developmental abnormalities remain unclear.
Purpose of the Study:
- To investigate cell-type-specific abnormalities in early brain development in Down syndrome.
- To explore the molecular mechanisms contributing to cognitive impairments in DS using cerebral organoids.
- To identify potential therapeutic targets for DS-related developmental defects.
Main Methods:
- Histological assays and single-cell RNA-sequencing (scRNA-Seq) were performed on cerebral organoids.
- Organoids were derived from both euploid cell lines and induced pluripotent stem cells (iPSCs) from individuals with trisomy 21.
- CRISPR/Cas9, CRISPR interference (CRISPRi), and small-molecule inhibitors were used to modulate the DSCAM/PAK1 pathway.
Main Results:
- Neurogenesis was significantly impaired in DS organoids, characterized by reduced proliferation and decreased expression of specific cortical neuron markers.
- DS organoids exhibited reduced size, potentially due to the observed neurogenesis defects.
- Enhanced activity of the DSCAM/PAK1 pathway was detected in DS models.
- Suppression of the DSCAM/PAK1 pathway reversed abnormal neurogenesis and increased organoid size in DS models.
Conclusions:
- 3D cerebral organoids serve as a valuable in vitro model for studying Down syndrome brain development.
- A direct link exists between the dysregulation of the DSCAM/PAK1 pathway and developmental brain defects in Down syndrome.
- Targeting the DSCAM/PAK1 pathway presents a potential therapeutic strategy for mitigating neurodevelopmental abnormalities in Down syndrome.
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