灰的功能丧失导致结构性出生缺陷和皮层发育的改变
Kevin P Toolan1, Brian T McGrath2, Michelle L Brinkmeier1
1Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI48109, USA.
Brain : a journal of neurology
|June 29, 2024
概括
基因组甲基转移酶ASH1L对于产后生存和正常的面发育至关重要. 大脑中的ASH1L功能丧失会扰乱上层皮质神经元的发育,影响基因表达和细胞分化轨迹.
科学领域:
- 神经科学是一个神经科学.
- 发育生物学 发展生物学
- 遗传学 是一个遗传学.
背景情况:
- 基因组甲基转移酶ASH1L在发育过程中对基因调节至关重要.
- ASH1L变种与自闭症谱系障碍有关,但其在大脑发育中的作用尚不清楚.
- 以前对小鼠的研究表明,Ash1l缺乏导致了自闭症类行为.
研究的目的:
- 调查Ash1l功能丧失对生存和面骨发育的影响.
- 分析Ash1l在皮层发育和神经元分化中的作用.
- 探索ASH1L在大脑中的功能背后的分子机制.
主要方法:
- 使用一种可诱导创建的Ash1l淘汰赛小鼠模型 (Ash1l exon 4删除).
- 用于早期皮质发育向 (Emx1-Cre-ERT2; e10.5) 的托莫西芬.
- 采用免疫组织化学,用于出生日期的EDU结合,以及单细胞RNA测序.
主要成果:
- 同胞卵性Ash1l淘汰胚胎显示没有产后存活,尽管胚胎比例正常.
- 灰1l无菌小鼠表现出缩短的鼻骨和改变的面发育.
- 皮层特异性淘汰导致SATB2+神经元增加,宫外深层神经元增加,上层神经元的基因表达改变,表明分化中断.
结论:
- 灰对于产后生存和正常的面发育至关重要.
- ASH1L对于适当的上层皮质神经元命运决定和基因表达是不可或缺的.
- 研究结果提供了关于ASH1L在神经发育障碍,包括自闭症中的作用的见解.
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