Brain transcriptome analysis of Myt1l heterozygote mutation mice in different brain regions (RNA-Seq II)

Myt1l, a zinc-finger transcription factor, promotes neuronal differentiation and is implicated in autism spectrum disorders (ASD) and intellectual disability. However, it was previously unclear whether Myt1l promotes neuronal differentiation in vivo, how its deficiency leads to disease-related mouse phenotypes, and whether and how ASD-risk genes with strong embryonic and perinatal gene expression can yield strong adult-stage ASD-related phenotypes. Here, we report that Myt1l-heterozygous knockout (Myt1l-HT) mice display postnatal age-differential ASD-like phenotypes: Newborn Myt1l-HT mice show ASD-like transcriptomic changes involving suppressed neuronal and synaptic gene expression and suppressed right reflex. Juvenile Myt1l-HT mice display mixed ASD-like and reverse-ASD transcriptomic patterns and large normal behaviors, accompanying increased prefrontal excitatory synaptic transmission. However, adult Myt1l-HT mice show additional ASD-like transcriptomic changes involving astrocytic and microglial genes, along with behavioral deficits and excessive prefrontal inhibitory synaptic transmission. Therefore, Myt1l HT leads to newborn-stage ASD-like neuronal suppression, temporary juvenile normalization, and subsequent adult-stage ASD-like deficits. Sub-brain transcriptome of Myt1l heterozygote mutation mice in prefrontal cortex, hippocampus, and striatumMyt1l作为一种锌指转录因子（zinc-finger transcription factor），可促进神经元分化，并与自闭症谱系障碍（ASD）及智力障碍密切相关。然而此前学界尚不明确：Myt1l是否可在体内促进神经元分化、其缺陷如何引发疾病相关小鼠表型，以及在胚胎和围产期高表达的自闭症风险基因，能否并如何在成年阶段引发类ASD表型。本研究显示，Myt1l杂合敲除（Myt1l-HT）小鼠呈现出生后阶段性的类ASD表型：新生Myt1l-HT小鼠出现以神经元与突触基因表达受抑制、翻正反射（right reflex）受损为特征的类ASD转录组变化；幼年Myt1l-HT小鼠呈现混合的类ASD与反向ASD转录组模式，行为表现基本正常，同时伴随前额叶兴奋性突触传递增强。而成年Myt1l-HT小鼠则出现额外的类ASD转录组变化，涉及星形胶质细胞与小胶质细胞相关基因，同时表现出行为缺陷及前额叶抑制性突触传递过度增强。综上，Myt1l杂合缺失会导致新生阶段类ASD样神经元抑制、幼年阶段的暂时性正常化，以及后续成年阶段的类ASD样缺陷。本数据集为Myt1l杂合突变小鼠前额叶皮层、海马体与纹状体的脑亚区域转录组。