美国加州大学旧金山分校Arnold R. Kriegstein等共同合作，近期取得重要工作进展。他们研究提出了人类新皮质发育过程中的分子与细胞动态变化。相关研究成果2025年1月8日在线发表于《自然》杂志上。

据介绍，人类新皮质的发育极具动态性，涉及由基因调控控制的复杂细胞轨迹。

研究人员收集了来自38个人类新皮层样本的配对单核染色质可及性和转录组数据，这些样本涵盖了前额叶皮质和初级视觉皮质。这些样本跨越了从孕早期到青春期的五个主要发育阶段。同时，研究人员对部分样本进行了空间转录组分析，以阐释空间组织和细胞间通讯情况。这一图谱使研究人员能够对神经分化背后的细胞类型特异性、年龄特异性以及区域特异性的基因调控网络进行分类整理。

此外，通过结合单细胞分析、祖细胞纯化以及谱系追踪实验，研究人员解析了在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。研究人员鉴定出了一种三潜能中间祖细胞亚型（Tri-IPC），其负责在局部产生γ-氨基丁酸能神经元、少突胶质前体细胞和星形胶质细胞。大多数胶质母细胞瘤细胞在转录组水平上与Tri-IPC相似，这表明癌细胞会劫持发育过程以增强其生长和异质性。

此外，通过将这一图谱数据与大规模全基因组关联研究数据相结合，研究人员绘制了一幅疾病风险图谱，凸显了孕中期脑内神经元中与自闭症谱系障碍相关的富集风险。

总之，这一研究为正在发育的人类新皮层的分子和细胞动态变化提供了新的见解。

附：英文原文

Title: Molecular and cellular dynamics of the developing human neocortex

Author: Wang, Li, Wang, Cheng, Moriano, Juan A., Chen, Songcang, Zuo, Guolong, Cebrin-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.

Issue&Volume: 2025-01-08

Abstract: 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.

DOI: 10.1038/s41586-024-08351-7

Source: https://www.nature.com/articles/s41586-024-08351-7