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

Sci Adv. 2024 Jun 7;10(23):eadj0385. doi: 10.1126/sciadv.adj0385. Epub 2024 Jun 7.


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.

MeSH terms

  • Cell Differentiation* / genetics
  • Chromosomes, Human, Pair 21 / genetics
  • Down Syndrome* / genetics
  • Gene Dosage*
  • Humans
  • Induced Pluripotent Stem Cells* / cytology
  • Induced Pluripotent Stem Cells* / metabolism
  • Neurogenesis* / genetics
  • Neurons / metabolism
  • RNA, Long Noncoding* / genetics


  • RNA, Long Noncoding
  • XIST non-coding RNA