Wang Li, Wang Cheng, Moriano Juan A, Chen Songcang, Zuo Guolong, Cebrián-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
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA.
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
Nature. 2025 Jan 8. doi: 10.1038/s41586-024-08351-7.
The development of the human neocortex is highly dynamic, involving complex cellular trajectories controlled by gene regulation. 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.
人类新皮层的发育高度动态，涉及由基因调控控制的复杂细胞轨迹。在这里，我们从38个人类新皮层样本中收集了配对的单核染色质可及性和转录组数据，这些样本涵盖前额叶皮层和初级视觉皮层。这些样本跨越五个主要发育阶段，从妊娠早期到青春期。同时，我们对一部分样本进行了空间转录组分析，以阐明空间组织和细胞间通讯。这个图谱使我们能够编目神经分化过程中细胞类型特异性、年龄特异性和区域特异性的基因调控网络。此外，结合单细胞分析、祖细胞纯化和谱系追踪实验，我们解开了神经发生向胶质发生转变过程中祖细胞亚型之间复杂的谱系关系。我们鉴定出一种三能中间祖细胞亚型——三能中间祖细胞（Tri-IPC）——它负责局部产生γ-氨基丁酸能神经元、少突胶质细胞前体细胞和星形胶质细胞。值得注意的是，大多数胶质母细胞瘤细胞在转录组水平上类似于Tri-IPC，这表明癌细胞劫持发育过程以增强生长和异质性。此外，通过将我们的图谱数据与大规模全基因组关联研究数据整合，我们创建了一个疾病风险图谱，突出了妊娠中期脑内神经元中与自闭症谱系障碍相关的富集风险。我们的研究揭示了发育中的人类新皮层的分子和细胞动力学。
