Arid1a regulates neural stem/progenitor cell proliferation and differentiation during cortical development

作者：Xiao Liu, Shang‐Kun Dai, Peipei Liu, Chang‐Mei Liu · 发表于：Cell Proliferation · 年份：2021 · DOI：10.1111/cpr.13124 · 被引用次数：28 · 研究领域：Chromatin Remodeling and Cancer、Neurogenesis and neuroplasticity mechanisms、Genetics and Neurodevelopmental Disorders

OBJECTIVE: Neurodevelopmental diseases are common disorders caused by the disruption of essential neurodevelopmental processes. Recent human exome sequencing and genome-wide association studies have shown that mutations in the subunits of the SWI/SNF (BAF) complex are risk factors for neurodevelopmental diseases. Clinical studies have found that ARID1A (BAF250a) is the most frequently mutated SWI/SNF gene and its mutations lead to mental retardation and microcephaly. However, the function of ARID1A in brain development and its underlying mechanisms still remain elusive. METHODS: The present study used Cre/loxP system to generate an Arid1a conditional knockout mouse line. Cell proliferation, cell apoptosis and cell differentiation of NSPCs were studied by immunofluorescence staining. In addition, RNA-seq and RT-PCR were performed to dissect the molecular mechanisms of Arid1a underlying cortical neurogenesis. Finally, rescue experiments were conducted to evaluate the effects of Neurod1 or Fezf2 overexpression on the differentiation of NSPCs in vitro. RESULTS: Conditional knockout of Arid1a reduces cortical thickness in the developing cortex. Arid1a loss of function inhibits the proliferation of radial glial cells, and increases cell death during late cortical development, and leads to dysregulated expression of genes associated with proliferation and differentiation. Overexpression of Neurod1 or Fezf2 in Arid1a cKO NSPCs rescues their neural differentiation defect in vitro. CON...