TITLE: “Defining molecular dysregulation in Down Syndrome neocortex and neural progenitor cells.”
ABSTRACT: Down syndrome (DS) is the most common form of genetic, intellectual disability, which occurs 1 in 700 newborns and presents in patients as cognitive deficits, particularly diminished in learning, memory, and language development.1,2,3 DS symptoms result from impaired cortical development, which is demonstrated, in contrast to neurotypical (NTD) brains, by postnatally reduced whole brain weight, volume and surface area, lower numbers of progenitors, excitatory neurons and oligodendrocytes, increased numbers of astrocytes, interneurons and microglia, and altered neuronal morphology, maturation, and migration.3–10 These DS neuropathologies result through some means from the triplication of human chromosome 21 (hsa21) or trisomy 21 (T21). However, the way in which T21 confers DS pathology and inhibits cortical development remains unclear. I hypothesize that increased hsa21 gene dosage alters global gene expression in neural progenitors, changing neural cell fate specification and differentiation. By single nuclei Multiome sequencing, T21 neocortices demonstrate a disproportionate increase in progenitors, interneurons and oligodendrocyte precursor cells and decrease in excitatory neurons, contrast to neurotypical (NT) donors. Furthermore, T21 neocortices show cell-specific differential expression of critical neurodevelopmental genes and transcription factors. These data support potential, cell-specific mechanisms of gene dysregulation during T21 neurodevelopment.
