ARID1A是一种常见的突变于癌症中的SWI/SNF染色质重塑基因，被假设为肿瘤抑制基因。最近，研究表明ARID1A基因的功能丧失导致智力障碍。在这里，我们生成了Arid1a条件性敲除小鼠，并在海马中研究了Arid1a的功能。在小鼠前脑中破坏Arid1a明显减少了神经干/祖细胞(NSPCs)的增殖和分化成为齿状回(DG)神经元，增加了围生期和产后凋亡，导致海马体积减小。此外，我们进行了单细胞RNA测序(scRNA-seq)以研究细胞异质性，并揭示Arid1a对DG祖细胞池的维持和有丝分裂后神经元的存活至关重要。转录组和ChIP-seq分析数据表明ARID1A通过改变组蛋白修饰水平来特异性调节Prox1。下游靶基因Prox1的过表达可以挽救由Arid1a删除引起的NSPCs增殖和分化缺陷。从总体上看，我们的结果表明Arid1a在海马发育中起到重要作用，同时也可能为Coffin-Siris综合征等智力障碍的遗传基础提供了新的见解。© 2023. 作者，独家授权给ADMC细胞分化和死亡协会。

ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be a tumor suppressor. Recently, loss-of-function of ARID1A gene has been shown to cause intellectual disability. Here we generate Arid1a conditional knockout mice and investigate Arid1a function in the hippocampus. Disruption of Arid1a in mouse forebrain significantly decreases neural stem/progenitor cells (NSPCs) proliferation and differentiation to neurons within the dentate gyrus (DG), increasing perinatal and postnatal apoptosis, leading to reduced hippocampus size. Moreover, we perform single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and reveal that Arid1a is necessary for the maintenance of the DG progenitor pool and survival of post-mitotic neurons. Transcriptome and ChIP-seq analysis data demonstrate that ARID1A specifically regulates Prox1 by altering the levels of histone modifications. Overexpression of downstream target Prox1 can rescue proliferation and differentiation defects of NSPCs caused by Arid1a deletion. Overall, our results demonstrate a critical role for Arid1a in the development of the hippocampus and may also provide insight into the genetic basis of intellectual disabilities such as Coffin-Siris syndrome, which is caused by germ-line mutations or microduplication of Arid1a.© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.