Astorkia Maider, Liu Yang, Pedrosa Erika M, Lachman Herbert M, Zheng Deyou
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine, Bronx, NY, USA.
bioRxiv. 2023 Sep 27:2023.09.27.559752. doi: 10.1101/2023.09.27.559752.
About 100 genes have been associated with significantly increased risks of autism spectrum disorders (ASD) with an estimate of ~1000 genes that may be involved. The new challenge now is to investigate the molecular and cellular functions of these genes during neural and brain development, and then even more challenging, to link the altered molecular and cellular phenotypes to the ASD clinical manifestations. In this study, we use single cell RNA-seq analysis to study one of the top risk gene, , in cerebral organoids, which models early neural development. We identify 21 cell clusters in the organoid samples, representing non-neuronal cells, neural progenitors, and early differentiating neurons at the start of neural cell fate commitment. Comparisons of the cells with one copy of the knockout and their isogenic controls uncover thousands of differentially expressed genes, which are enriched with function related to neural and brain development, with genes and pathways previously implicated in ASD, but surprisingly not for Schizophrenia and intellectual disability risk genes. The comparisons also find cell composition changes, indicating potential altered neural differential trajectories upon reduction. Moreover, we find that cell-cell communications are affected in the knockout organoids, including the interactions between neural and glial cells. Taken together, our results provide new data for understanding CHD8 functions in the early stages of neural lineage development and interaction.
约100个基因已被证实与自闭症谱系障碍（ASD）风险显著增加相关，据估计可能涉及约1000个基因。当前新的挑战是研究这些基因在神经和大脑发育过程中的分子和细胞功能，而更具挑战性的是，将改变的分子和细胞表型与ASD临床表现联系起来。在本研究中，我们使用单细胞RNA测序分析来研究大脑类器官（其模拟早期神经发育）中一个最重要的风险基因CHD8。我们在类器官样本中鉴定出21个细胞簇，它们代表神经细胞命运决定开始时的非神经元细胞、神经祖细胞和早期分化神经元。对携带一个CHD8基因敲除拷贝的细胞与其同基因对照进行比较，发现了数千个差异表达基因，这些基因富集于与神经和大脑发育相关的功能，以及先前与ASD相关的基因和通路，但令人惊讶的是，未涉及精神分裂症和智力残疾风险基因。这些比较还发现了细胞组成的变化，表明CHD8基因减少后神经分化轨迹可能发生改变。此外，我们发现CHD8基因敲除的类器官中细胞间通讯受到影响，包括神经细胞与神经胶质细胞之间的相互作用。综上所述，我们的结果为理解CHD8在神经谱系发育和相互作用早期阶段的功能提供了新的数据。
