Variation of human neural stem cells generating organizer states in vitro before committing to cortical excitatory or inhibitory neuronal fates [mouse RNAseq]

Better understanding the progression of neural stem cells (NSCs) in the developing cerebral cortex is important for modeling neurogenesis and defining the pathogenesis of neuropsychiat-ric disorders. Here we used RNA-sequencing, cell imaging and lineage tracing of mouse and human in vitro NSCs to model the generation of cortical neuronal fates. We show that con-served signaling mechanisms regulate the acute transition from proliferative NSCs to commit-ted glutamatergic excitatory neurons. As human telencephalic NSCs developed from pluripo-tentcy in vitro, they first transitioned through organizer states that spatially pattern the cortex before generating glutamatergic precursor fates. NSCs derived from multiple human pluripotent lines varied in these early states leading differentially to dorsal or ventral telencephalic fates. This work furthers systematic analysis of the earliest patterning events that generate the major neuronal trajectories of the human telencephalon. The gene amplitudes for the GWCoGAPS patterns in this data can be found in the supplemental files.

深入解析发育大脑皮层中神经干细胞（Neural Stem Cells, NSCs）的动态进程，对于构建神经发生模型以及阐明神经精神疾病的发病机制具有重要意义。本研究采用RNA测序、细胞成像及谱系示踪技术，对小鼠和人类体外培养的神经干细胞进行分析，以构建皮层神经元命运的生成模型。研究发现，保守的信号通路机制调控增殖态神经干细胞向定向分化的谷氨酸能兴奋性神经元的快速转变。当人类端脑神经干细胞从体外多能性状态发育时，其首先通过组织者状态完成皮层的空间模式构建，随后才生成谷氨酸能前体细胞命运。源自多株人类多能干细胞系的神经干细胞，在上述早期状态中存在差异，进而分别偏向背侧或腹侧端脑命运的生成。本研究进一步推进了对人类端脑主要神经元轨迹生成的早期模式构建事件的系统性分析。本数据集内GWCoGAPS模式的基因振幅数据可在补充材料中获取。