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Cited by 15Down syndrome and intellectual disability researchPluripotent Stem Cells ResearchDevelopmental Biology and Gene Regulation

Transcriptional consequences of trisomy 21 on neural induction

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Martinez, José L., Piciw, Jennifer G., Crockett, Madeline, Sorci, Isabella A., Makwana, Nikunj, Sirois, Carissa L., Giffin-Rao, Yathindar, Bhattacharyya, Anita·2024·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2024.1341141PMC PMC10865501
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Abstract

Introduction: Down syndrome, caused by trisomy 21, is a complex developmental disorder associated with intellectual disability and reduced growth of multiple organs. Structural pathologies are present at birth, reflecting embryonic origins. A fundamental unanswered question is how an extra copy of human chromosome 21 contributes to organ-specific pathologies that characterize individuals with Down syndrome, and, relevant to the hallmark intellectual disability in Down syndrome, how trisomy 21 affects neural development. We tested the hypothesis that trisomy 21 exerts effects on human neural development as early as neural induction. Methods: Bulk RNA sequencing was performed on isogenic trisomy 21 and euploid human induced pluripotent stem cells (iPSCs) at successive stages of neural induction: embryoid bodies at Day 6, early neuroectoderm at Day 10, and differentiated neuroectoderm at Day 17. Results: Gene expression analysis revealed over 1,300 differentially expressed genes in trisomy 21 cells along the differentiation pathway compared to euploid controls. Less than 5% of the gene expression changes included upregulated chromosome 21 encoded genes at every timepoint. Genes involved in specific growth factor signaling pathways (WNT and Notch), metabolism (including oxidative stress), and extracellular matrix were altered in trisomy 21 cells. Further analysis uncovered heterochronic expression of genes. Conclusion: Trisomy 21 impacts discrete developmental pathways at the earliest stages of neural development. The results suggest that metabolic dysfunction arises early in embryogenesis in trisomy 21 and may affect development and function more broadly.

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Authors
Martinez, J. L., Piciw, J. G., Crockett, M., Sorci, I. A., Makwana, N., Sirois, C. L., Giffin-Rao, Y., & Bhattacharyya, A.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
Bhattacharyya, Anita
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2024-01-30
Volume
18
Pages
1341141-1341141
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2024.1341141
PMC
PMC10865501
OpenAlex
W4391358880
Cited by
15
References
83
Citations by year
2026: 4 · 2025: 7 · 2024: 4
FWCI
6.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • University of Wisconsin-Madison
  • Waisman Center (P50HD105353)
  • National Institutes of Health (NIH 5 T32)
  • National Institute on Aging (R36AG072108)
  • National Institute of General Medical Sciences (T32GM008349, T32GM135066, T32GM140935)
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD111938, P50HD105353, R01HD106197)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
Down syndrome, neural induction, neural development, gene expression, embryoid bodies, neuroectoderm differentiation, Wnt signaling, Notch signaling, oxidative stress, extracellular matrix, metabolic dysfunction, intellectual disability

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