ASH1L Haploinsufficiency Results in Autistic-like Phenotypes in Mice And Links Eph Receptor Gene To Autism Spectrum Disorder
Mar 23, 2022
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Yuze Yan, Miaomiao Tian, Meng Li, Wei Xiong, Shiguo Liu, Ji-Song Guan
Introduction
Group protein methylation is used as an apparent genetic mechanism that plays an important role in gene expression and silencing, cell differentiation, and gene blotting. The histone methyltransferase ASH1L is closely related to intellectual disorders, autism. The apparent genetic regulatory factor can adjust synaptic development and synaptic plasticity to participate in higher-level cognitive functions. Succession and shear (excessive or too little synaptic) from an abnormal neural ring have become the main pathological mechanism of autism.
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Result
Ash1l knockout mice died in embryos, but haploid mutant (Ash1l +/-) mice survived. Through a series of behavioral experiments, it was found that Ash1l +/- mice had autistic behavior disorders such as repetitive behavior disorder, social disorder, and developmental disorder, as well as anxious behavior.
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In situ hybridization showed that Ash1l was mainly expressed in neurons. Compared with normal mice, the density of dendritic spines of neurons in cortical and dorsal striatum regions of 1-month-old Ash1l +/- mice was significantly increased, which may be caused by the reduced synaptic pruning function.
To confirm this hypothesis, in vitro culture, it was found that the rate of elimination of posterior axon nodule in photoactivated neurons of Ash1l +/- mouse origin was lower. After aAV-HSYN-Cre and AAV-EF1A-Dio-EYFP specific knockout neurons, Ash1l were injected into the auditory cortex, the elimination rate of axon nodule in the knockout mice was also lower after auditory training. This suggests that there is a neuronal activity-dependent synaptic pruning disorder in Ash1l +/- mouse cortex.
In order to find out the molecular mechanism of Ash1l mediating synaptic pruning disorder, we found that the EphA7 gene had spatiotemporal common differential expression among many differentially expressed genes by single-cell sequencing. 1. Regional commonality: down-regulated expression in auditory cortex and dorsal striatum; 2. Time-age commonality: Ash1l +/- was down-regulated in both 1-month-old and 12-month-old mice.
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The tyrosine kinase receptor EphA7, a member of the Ephrin receptor subfamily, plays a role in cortical development and synaptic function. Using fluorescently activated cell sorting, the researchers found that neurons activated by normal mice expressed high levels of EphA7, while neurons not activated expressed low levels of EphA7.
Summary
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 the 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 the 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.
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