Arid1a regulates neural stem/progenitor cell proliferation and differentiation during cortical development.
Arid1a regulates neural stem/progenitor cell proliferation and differentiation during cortical development.
复制标题
Arid1a 调节皮质发育过程中的神经干/祖细胞增殖和分化
DOI：
10.1111/cpr.13124
复制
发表时间：
2021-11
影响因子：
8.5
通讯作者：
Liu CM
中科院分区：
文献类型：
--
作者：
Liu X;Dai SK;Liu PP;Liu CM
神经发育疾病是由基本神经发育过程破坏引起的常见疾病。最近的人类外显子组测序和全基因组关联研究表明，SWI/SNF (BAF) 复合体亚基的突变是神经发育疾病的危险因素。临床研究发现ARID1A（BAF250a）是最常突变的SWI/SNF基因，其突变会导致智力低下和小头畸形。然而，ARID1A 在大脑发育中的功能及其潜在机制仍不清楚。本研究使用Cre/loxP系统生成Arid1a条件敲除小鼠品系。通过免疫荧光染色研究NSPCs的细胞增殖、细胞凋亡和细胞分化。此外，还进行了 RNA-seq 和 RT-PCR 来剖析 Arid1a 潜在皮质神经发生的分子机制。最后，进行拯救实验来评估Neurod1或Fezf2过表达对NSPCs体外分化的影响。有条件地敲除 Arid1a 会减少发育中皮质的皮质厚度。 Arid1a 功能丧失会抑制放射状胶质细胞的增殖，并增加皮质发育后期的细胞死亡，并导致与增殖和分化相关的基因表达失调。 Arid1a cKO NSPC 中 Neurod1 或 Fezf2 的过度表达可在体外挽救其神经分化缺陷。该研究首次证明Arid1a在调节皮质发育过程中NSPC的增殖和分化中发挥重要作用，并提出了几个候选基因，这些候选基因值得了解其病理机制并开发针对Arid1a突变引起的神经发育障碍的新干预措施。尽管Arid1a突变与智力低下和小头畸形密切相关，但Arid1a在大脑发育中的功能及其潜在机制仍然难以捉摸。本研究首次证明Arid1a在调节皮质发育过程中神经干/祖细胞的增殖和分化中发挥重要作用，并提出了几个候选基因，这些候选基因值得了解其病理机制并开发针对Arid1a突变引起的神经发育障碍的新干预措施。
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. 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. 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. This study demonstrates for the first time that Arid1a plays an important role in regulating the proliferation and differentiation of NSPCs during cortical development, and proposes several gene candidates that are worth to understand the pathological mechanisms and to develop novel interventions of neurodevelopment disorders caused by Arid1a mutations. Although Arid1a mutations are closely related to mental retardation and microcephaly, the function of Arid1a in brain development and its underlying mechanisms still remain elusive. The present study demonstrates for the first time that Arid1a plays an important role in regulating the proliferation and differentiation of neural stem/progenitor cells during cortical development, and proposes several gene candidates that are worth to understand the pathological mechanisms and to develop novel interventions of neurodevelopment disorders caused by Arid1a mutations.
登录
查看更多内容
遗传变化塑造了人脑。
影响因子：
11.8
作者：
Bae BI;Jayaraman D;Walsh CA
通讯作者：
Walsh CA
影响因子：
2.7
作者：
Chandler RL;Magnuson T
通讯作者：
Magnuson T
影响因子：
16.6
作者：
Gatchalian J;Malik S;Ho J;Lee DS;Kelso TWR;Shokhirev MN;Dixon JR;Hargreaves DC
通讯作者：
Hargreaves DC
MiR-203 与 Polycomb 抑制复合物相互作用调节神经干/祖细胞的增殖
影响因子：
5.9
作者：
Liu PP;Tang GB;Xu YJ;Zeng YQ;Zhang SF;Du HZ;Teng ZQ;Liu CM
通讯作者：
Liu CM
影响因子：
16.2
作者：
Guo C;Eckler MJ;McKenna WL;McKinsey GL;Rubenstein JL;Chen B
通讯作者：
Chen B