Single-cell atlas of the developing Down syndrome brain cortex
Michael Lattke, Wee Leng Tan, Salil Kalarikkal Sukumaran, Kagistia Hana Utami, Marcos Sintes, Srinivasan Sakthivel, Jonathan Tan, Auriel Lim, Vibhavari Aysha Bansal, Katerina Rekopoulou, Nik Matthews, Ivan Alić, Željka Krsnik, Dean Nižetić, Boaz P. Levi, Vincenzo De Paola
TL;DR
This study uses single-cell analysis to uncover how Down syndrome disrupts brain development, identifying key genes and pathways involved.
Contribution
The study identifies three dosage-sensitive transcription factors on chromosome 21 that drive neurodevelopmental disruptions in Down syndrome.
Findings
A subtype-specific reduction in RORB- and FOXP1-expressing excitatory neurons was observed in Down syndrome fetal cortices.
Transcription factors BACH1, PKNOX1, and GABPA were found to regulate genes linked to intellectual disability in Down syndrome.
Antisense oligonucleotide treatment partially rescued gene expression in human neural progenitors in vitro.
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…
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Taxonomy
TopicsDown syndrome and intellectual disability research · Single-cell and spatial transcriptomics · Williams Syndrome Research