Single-cell analysis of prenatal and postnatal human cortical development

Dmitry Velmeshev, Yonatan Perez, Zihan Yan, Jonathan E. Valencia, David R. Castaneda-Castellanos, Li Wang, Lucas Schirmer, Simone Mayer, Brittney Wick, Shaohui Wang, Tomasz Jan Nowakowski, Mercedes Paredes, Eric J Huang, Arnold R Kriegstein
bioRxiv (2023)


We analyze more than 700,000 single-nucleus RNA-seq profiles from 106 donors during prenatal and postnatal developmental stages and identify lineage-specific programs that underlie the development of specific subtypes of excitatory cortical neurons, interneurons, glial cell types and brain vasculature. By leveraging single-nucleus chromatin accessibility data, we delineate enhancer-gene regulatory networks and transcription factors that control commitment of specific cortical lineages. By intersecting our results with genetic risk factors for human brain diseases, we identify the cortical cell types and lineages most vulnerable to genetic insults of different brain disorders, especially autism. We find that lineage-specific gene expression programs upregulated in female cells are especially enriched for the genetic risk factors of autism. Our study captures the molecular progression of cortical lineages across human development.