2. Academic Validation
  3. 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

  • Neuron. 2022 Apr 6;110(7):1156-1172.e9. doi: 10.1016/j.neuron.2021.12.035.
Yuze Yan 1,  Miaomiao Tian 1,  Meng Li 2,  Gang Zhou 2,  Qinan Chen 2,  Mingrui Xu 3,  Yi Hu 1,  Wenhan Luo 2,  Xiuxian Guo 2,  Cheng Zhang 4,  Hong Xie 5,  Qing-Feng Wu 6,  Wei Xiong 7,  Shiguo Liu 8,  Ji-Song Guan 9
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3 State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China.
  • 4 Medical Genetic Department, the Affiliated Hospital of Qingdao University, Qingdao, 266071, China; The Prenatal Diagnosis Center, the Affiliated Hospital of Qingdao University, Qingdao, 266071, China.
  • 5 Institute of Photonic Chips, University of Shanghai for Science and Technology, Shanghai 200093, China; School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
  • 6 CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China.
  • 7 School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
  • 8 Medical Genetic Department, the Affiliated Hospital of Qingdao University, Qingdao, 266071, China; The Prenatal Diagnosis Center, the Affiliated Hospital of Qingdao University, Qingdao, 266071, China. Electronic address: [email protected].
  • 9 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: [email protected].
PMID: 35081333 DOI: 10.1016/j.neuron.2021.12.035
Abstract

ASD-associated genes are enriched for synaptic proteins and epigenetic regulators. How those chromatin modulators establish ASD traits have remained unknown. We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior, including repetitive behavior, and alters social behavior. Specific depletion of Ash1l in forebrain induces similar ASD-associated behavioral defects. While the learning ability remains intact, the discrimination ability of Ash1l mutant mice is reduced. Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period. Dysregulation of synaptic genes is detected in Ash1l mutant brain. Specifically, Eph receptor A7 is downregulated in Ash1l+/- mice through accumulating EZH2-mediated H3K27me3 in its gene body. Importantly, increasing activation of EphA7 in Ash1l+/- mice by supplying its ligand, Ephrin-A5, strongly promotes synapse pruning and rescues discrimination deficits. Our results suggest that Ash1l haploinsufficiency is a highly penetrant risk factor for ASD, resulting from synapse pruning deficits.

Keywords

Ash1l; autism spectrum disorder; epigenetics; in vivo imaging; synapse; synapse pruning.

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