State Key Laboratory of Cognitive Neuroscience and Learning, New Cornerstone Science Laboratory, Beijing Normal University, Beijing, 100875, China.
IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, 100875, China.
Nat Commun. 2023 Nov 22;14(1):7613. doi: 10.1038/s41467-023-43568-6.
Human cerebellar development is orchestrated by molecular regulatory networks to achieve cytoarchitecture and coordinate motor and cognitive functions. Here, we combined single-cell transcriptomics, spatial transcriptomics and single cell chromatin accessibility states to systematically depict an integrative spatiotemporal landscape of human fetal cerebellar development. We revealed that combinations of transcription factors and cis-regulatory elements (CREs) play roles in governing progenitor differentiation and cell fate determination along trajectories in a hierarchical manner, providing a gene expression regulatory map of cell fate and spatial information for these cells. We also illustrated that granule cells located in different regions of the cerebellar cortex showed distinct molecular signatures regulated by different signals during development. Finally, we mapped single-nucleotide polymorphisms (SNPs) of disorders related to cerebellar dysfunction and discovered that several disorder-associated genes showed spatiotemporal and cell type-specific expression patterns only in humans, indicating the cellular basis and possible mechanisms of the pathogenesis of neuropsychiatric disorders.
人类小脑的发育是由分子调控网络协调的，以实现细胞结构和协调运动和认知功能。在这里，我们结合单细胞转录组学、空间转录组学和单细胞染色质可及性状态，系统地描绘了人类胎儿小脑发育的综合时空景观。我们揭示了转录因子和顺式调控元件（CREs）的组合在沿着层次轨迹控制祖细胞分化和细胞命运决定方面发挥作用，为这些细胞的细胞命运和空间信息提供了基因表达调控图谱。我们还表明，位于小脑皮层不同区域的颗粒细胞在发育过程中受到不同信号的调控，表现出不同的分子特征。最后，我们绘制了与小脑功能障碍相关疾病的单核苷酸多态性（SNPs）图谱，发现几种与疾病相关的基因仅在人类中表现出时空和细胞类型特异性表达模式，这表明了神经精神疾病发病机制的细胞基础和可能的机制。
