Transcriptional consequences of trisomy 21 on neural induction
Year: 2024
Type: article
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.
Authors: José L. Martinez, Jennifer G. Piciw, Madeline Crockett, Isabella A. Sorci, Nikunj Makwana, Carissa L. Sirois, Yathindar Giffin-Rao, Anita Bhattacharyya
Institution: University of Wisconsin–Madison
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,295
Funders: University of Wisconsin-Madison, Waisman Center, National Institutes of Health, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1236303967, G3142106742, Biotechnology Training Program, Modeling Basal Forebrain Cholinergic Neurons in Down syndrome, A heterochronic model for birth defects in Down Syndrome, Biotechnology Training Program, Integrated Training For Physician-Scientists, Waisman Center Intellectual and Developmental Disabilities Research Center, Human cortical development and neural plasticity altered by trisomy 21
OpenAlex ID: W4391358880