Single-cell atlas of the developing Down syndrome brain cortex
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Down syndrome (DS), caused by trisomy of chromosome 21, is the leading genetic cause of intellectual disability, yet the mechanisms disrupting fetal brain development remain unclear. We performed single-cell transcriptomic and chromatin accessibility profiling of approximately 250,000 cells from 15 DS and 15 control human fetal cortices (10–20 weeks postconception). Our analysis revealed a subtype-specific reduction in RORB- and FOXP1-expressing excitatory neurons and widespread disruption of neurodevelopmental transcriptional programs. Chromosome 21 transcription factors BACH1, PKNOX1 and GABPA emerged as dosage-sensitive hubs regulating genes linked to intellectual disability. Antisense oligonucleotide-mediated normalization of these transcription factors in human neural progenitors in vitro partially rescued target gene expression. Benchmarking a humanized in vivo model captured additional molecular and cellular signatures of DS, complementing the in vitro model. Together, we present a resource defining the gene-regulatory landscape underlying cortical development in DS and highlight molecular pathways for further investigation.
Date Issued
2026-03-01
Date Acceptance
2026-01-09
Citation
Nature Medicine, 2026, 32 (3), pp.1061-1072
ISSN
1078-8956
Publisher
Springer Science and Business Media LLC
Start Page
1061
End Page
1072
Journal / Book Title
Nature Medicine
Volume
32
Issue
3
Copyright Statement
© The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41545595
PII: 10.1038/s41591-026-04211-1
Subjects
Humans
Down Syndrome
Cerebral Cortex
Single-Cell Analysis
Animals
Gene Expression Regulation, Developmental
Single-Cell Gene Expression Analysis
Neurons
Neurodevelopment
Female
Neural Stem Cells
Transcriptome
Transcription Factors
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2026-01-16