自闭症基因在共享神经元类别的异步发展上趋同
Bruna Paulsen1,2, Silvia Velasco3,4,5, Amanda J Kedaigle1,2,6
1Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Nature
|February 3, 2022
概括
自闭症谱系障碍 (ASD) 风险基因导致人类大脑器官的异步神经元发育. 这些由个体遗传学影响的细胞特异性缺陷导致异常电路活动,
科学领域:
- 神经科学
- 遗传学
- 发育生物学
背景情况:
- 自闭症谱系障碍 (ASD) 风险涉及数百个具有不同功能的基因.
- 这些遗传突变引起的特定大脑变化和可变表型尚未完全理解.
研究的目的:
- 在人类大脑皮层的器官中发现细胞类型特定的发育异常,这些异常是由于三种自闭症风险基因SUV420H1,ARID1B和CHD8的哈普洛缺陷造成的.
- 研究表型的融合以及个体基因组背景对自闭症病理学的影响.
主要方法:
- 使用来自多个细胞系和捐赠者的人类大脑皮质器官模型.
- 在超过745,000个细胞上进行单细胞RNA测序 (scRNA-seq).
- 对单个有机体进行蛋白质分析和成像,以评估电路活性.
主要成果:
- 在SUV420H1,ARID1B和CHD8中,Haploinsufficiency导致GABAergic和深层刺激投射神经元的异步发育.
- 每个基因都涉及不同的分子通路,但仍观察到表型的融合.
- 发育缺陷在细胞系中是一致的,但因个体基因组背景而改变.
- 在有机体模型中与异常电路活动相关的早期发育变化.
结论:
- 自闭症风险基因可能导致细胞类型特异的神经发育异常.
- 这些异常显示出它们对自闭症病理的贡献趋同.
- 个体基因组背景显著调节与自闭症相关的发育缺陷的表达性.
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