The mammalian prefrontal cortex comprises a set of highly specialized brain areas containing billions of cells and serves as the centre of the highest-order cognitive functions, such as memory, cognitive ability, decision-making and social behaviour. Although neural circuits are formed in the late stages of human embryonic development and even after birth, diverse classes of functional cells are generated and migrate to the appropriate locations earlier in development. Dysfunction of the prefrontal cortex contributes to cognitive deficits and the majority of neurodevelopmental disorders; there is therefore a need for detailed knowledge of the development of the prefrontal cortex. However, it is still difficult to identify cell types in the developing human prefrontal cortex and to distinguish their developmental features. Here we analyse more than 2,300 single cells in the developing human prefrontal cortex from gestational weeks 8 to 26 using RNA sequencing. We identify 35 subtypes of cells in six main classes and trace the developmental trajectories of these cells. Detailed analysis of neural progenitor cells highlights new marker genes and unique developmental features of intermediate progenitor cells. We also map the timeline of neurogenesis of excitatory neurons in the prefrontal cortex and detect the presence of interneuron progenitors in early developing prefrontal cortex. Moreover, we reveal the intrinsic development-dependent signals that regulate neuron generation and circuit formation using single-cell transcriptomic data analysis. Our screening and characterization approach provides a blueprint for understanding the development of the human prefrontal cortex in the early and mid-gestational stages in order to systematically dissect the cellular basis and molecular regulation of prefrontal cortex function in humans.

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人类前额叶皮层发育景观的单细胞 RNA-seq 调查

哺乳动物前额叶皮层由一组高度专业化的大脑区域组成，其中包含数十亿个细胞，是最高阶认知功能的中心，例如记忆力、认知能力、决策和社会行为。尽管神经回路是在人类胚胎发育的后期甚至出生后形成的，但在发育的早期会产生不同类别的功能细胞并迁移到适当的位置。前额叶皮层功能障碍导致认知缺陷和大多数神经发育障碍；因此，需要详细了解前额叶皮层的发育。然而，在发育中的人类前额叶皮层中识别细胞类型并区分它们的发育特征仍然很困难。在这里，我们使用 RNA 测序分析了从妊娠第 8 周到第 26 周发育中的人类前额叶皮层中的 2,300 多个单细胞。我们确定了六个主要类别中的 35 种细胞亚型，并追踪了这些细胞的发育轨迹。对神经祖细胞的详细分析突出了中间祖细胞的新标记基因和独特的发育特征。我们还绘制了前额叶皮层中兴奋性神经元的神经发生时间线，并检测了早期发育的前额叶皮层中中间神经元祖细胞的存在。此外，我们使用单细胞转录组数据分析揭示了调节神经元生成和电路形成的内在发育依赖性信号。