Molecular and cellular dynamics of the developing human neocortex

• 成果类型: Article
• 署名作者: Wang, Li; Wang, Cheng; Moriano, Juan A.; Chen, Songcang; Zuo, Guolong; Cebrian-Silla, Arantxa; Zhang, Shaobo; Mukhtar, Tanzila; Wang, Shaohui; Song, Mengyi; de Oliveira, Lilian Gomes; Bi, Qiuli; Augustin, Jonathan J.; Ge, Xinxin; Paredes, Mercedes F.; Huang, Eric J.; Alvarez-Buylla, Arturo; Duan, Xin; Li, Jingjing; Kriegstein, Arnold R.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of Barcelona; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Universidade de Sao Paulo; Institute Biomed Science, University Sao Paulo; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-024-08351-7
• 发表日期: 2025-11-06
• 关键词: single-cell; neural stem; inference; package; lineage; variant

摘要

The development of the human neocortex is highly dynamic, involving complex cellular trajectories controlled by gene regulation1. Here we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and the primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence. In parallel, we performed spatial transcriptomic analysis on a subset of the samples to illustrate spatial organization and intercellular communication. This atlas enables us to catalogue cell-type-specific, age-specific and area-specific gene regulatory networks underlying neural differentiation. Moreover, combining single-cell profiling, progenitor purification and lineage-tracing experiments, we have untangled the complex lineage relationships among progenitor subtypes during the neurogenesis-to-gliogenesis transition. We identified a tripotential intermediate progenitor subtype-tripotential intermediate progenitor cells (Tri-IPCs)-that is responsible for the local production of GABAergic neurons, oligodendrocyte precursor cells and astrocytes. Notably, most glioblastoma cells resemble Tri-IPCs at the transcriptomic level, suggesting that cancer cells hijack developmental processes to enhance growth and heterogeneity. Furthermore, by integrating our atlas data with large-scale genome-wide association study data, we created a disease-risk map highlighting enriched risk associated with autism spectrum disorder in second-trimester intratelencephalic neurons. Our study sheds light on the molecular and cellular dynamics of the developing human neocortex.