Disruption of AT-hook 1 domain in MeCP2 protein caused behavioral abnormality in mice
Disruption of AT-hook 1 domain in MeCP2 protein caused behavioral abnormality in mice
复制标题
MeCP2蛋白中AT-hook 1结构域的破坏导致小鼠行为异常
DOI：
10.1016/j.bbadis.2017.10.022
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发表时间：
2018
影响因子：
6.2
通讯作者：
Hu Yafang
中科院分区：
文献类型：
--
作者：
Xu Miaojing;Song Pingping;Huang Wei;He Rongni;He Yong;Zhou Xiao;Gu Yong;Pan Suyue;Hu Yafang
mecp2是自闭症谱系障碍的致病基因，包括Rett综合征，这是一种主要发生在女孩身上的退行性神经发育罕见疾病。除了MeCP2中不同的甲基- cpg结合结构域和转录抑制结构域外，最近还发现了三个at -hook样结构域。在自闭症病例或Rett数据库中已经报道了AT-hook 1结构域的几个突变。然而，AT-hook 1结构域的作用尚不清楚。在这项研究中，我们通过聚集规则间隔短回文重复序列(CRISPR)/Cas9技术生成了一个携带AT-hook 1结构域8个保守氨基酸缺失的小鼠品系。Mecp2ΔAT-hook1/突变雄性小鼠表现出低运动活性、运动不协调和认知缺陷。此外，这些突变小鼠表现出更多的焦虑。此外，在突变雄性中发现疼痛不敏感。然而，AT-hook 1突变小鼠的社会互动不受影响。突变小鼠海马CA1区变薄。在分子基础上，Western blot分析显示突变MeCP2蛋白在皮层的表达增加。此外，大脑中抑制神经元中特异性表达的几个基因也发生了显著变化。综上所述，这些数据表明，MeCP2中AT-hook 1结构域的破坏导致小鼠行为异常，这表明AT-hook 1是MeCP2蛋白功能的关键区域。
MECP2is the causative gene for autism spectrum disorders, including Rett syndrome, a regressive neurodevelopmental rare disease mainly occurring in girls. Except for the distinct methyl-CpG binding domain and the transcriptional repression domain in MeCP2, three AT-hook-like domains have recently been identified. Several mutations in AT-hook 1 domain have been reported in autism cases or Rett database. However, the role of AT-hook 1 domain is still unclear. In this study, we generated a mouse line carrying deletion of eight conserved amino acids in AT-hook 1 domain by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology.Mecp2ΔAT-hook1/ymutant male mice exhibited low locomotor activity, motor incoordination and cognitive deficit. In addition, these mutant mice exhibited increased anxiety. Moreover, pain insensitivity was noted in the mutant males. However, the social interactions were unaffected in AT-hook 1 mutant mice. Thinner CA1 region of the hippocampus was observed in the mutant mice. On the molecular basis, Western blot analysis showed increased expression of mutant MeCP2 protein in the cortex. Additionally, several genes expressed specifically in inhibitory neurons were markedly changed in the cerebrum. Taken together, these data demonstrate that disruption of AT-hook 1 domain in MeCP2 caused behavioral abnormality in mice, which suggests that AT-hook 1 is a critical region for the function of MeCP2 protein.