ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder
ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder
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DOI：
10.1016/j.neuron.2021.12.035
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发表时间：
2022-01
期刊：
影响因子：
16.2
通讯作者：
Yuze Yan;Miaomiao Tian;Meng Li;Gang Zhou;Qi-Nan Chen;Mingrui Xu;Y. Hu;Wenhan Luo;Xiuxian Guo
中科院分区：
文献类型：
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作者：
Yuze Yan;Miaomiao Tian;Meng Li;Gang Zhou;Qi-Nan Chen;Mingrui Xu;Y. Hu;Wenhan Luo;Xiuxian Guo
ASD 相关基因富含突触蛋白和表观遗传调节因子。这些染色质调节剂如何建立 ASD 特征仍然未知。我们发现 Ash1l 的单倍体不足会导致焦虑和自闭症样行为，包括重复行为，并改变社会行为。 Ash1lin 前脑的特异性缺失会诱导类似的 ASD 相关行为缺陷。 Ash1l突变小鼠在学习能力保持不变的同时，辨别能力却下降。从机制上讲，由于突触修剪缺陷，Ash1lin 神经元的缺失会诱导过多的突触，尤其是在学习后阶段。在 Ash1l 突变大脑中检测到突触基因失调。具体而言，Eph 受体 A7 在 Ash1l+/- 小鼠中通过在其基因体中积累 EZH2 介导的 H3K27me3 而下调。重要的是，通过提供其配体肝配蛋白-A5，增加 Ash1l+/- 小鼠中 EphA7 的激活，强烈促进突触修剪并挽救辨别缺陷。我们的结果表明 Ash1l 单倍剂量不足是自闭症谱系障碍 (ASD) 的一个高度渗透性危险因素，是由突触修剪缺陷引起的。
ASD-associated genes are enriched for synaptic proteins and epigenetic regulators. How those chromatin modulators establish ASD traits have remained unknown. We find haploinsufficiency ofAsh1lcausally induces anxiety and autistic-like behavior, including repetitive behavior, and alters social behavior. Specific depletion ofAsh1lin forebrain induces similar ASD-associated behavioral defects. While the learning ability remains intact, the discrimination ability ofAsh1lmutant mice is reduced. Mechanistically, deletion ofAsh1lin neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period. Dysregulation of synaptic genes is detected inAsh1lmutant brain. Specifically, Eph receptor A7 is downregulated in Ash1l+/−mice through accumulating EZH2-mediated H3K27me3 in its gene body. Importantly, increasing activation ofEphA7in Ash1l+/−mice by supplying its ligand, ephrin-A5, strongly promotes synapse pruning and rescues discrimination deficits. Our results suggest thatAsh1lhaploinsufficiency is a highly penetrant risk factor for ASD, resulting from synapse pruning deficits.