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首页> 外文期刊>Nature >Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2
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Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2

机译：MeCP2过表达的转基因猴子中的自闭症样行为和种系传递

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摘要

Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing(1-4). Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes(5). Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders(6). Although Mecp2-null mice recapitulate most developmental and behavioural defects seen in patients with Rett syndrome, it has been difficult to identify autism-like behaviours in the mouse model of MeCP2 overexpression(7,8). Here we report that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wild-type monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test(9). The transgenic monkeys showed less interaction with wild-type monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviours. Notably, we succeeded in generating five F-1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from one F-0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F-1 progeny. Moreover, F-1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wild-type monkeys of similar age. Together, these results indicate the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.
机译：甲基CpG结合蛋白2（MeCP2）在转录调控和microRNA加工中具有关键作用（1-4）。在90％的Rett综合征患者中发现了MECP2基因突变，Rett综合征是一种具有自闭症表型的严重发育障碍（5）。包含MECP2的基因组片段重复会导致MECP2重复综合征，该综合征具有自闭症谱系障碍的核心症状（6）。尽管Mecp2无效的小鼠概括了在Rett综合征患者中见到的大多数发育和行为缺陷，但在MeCP2过表达的小鼠模型中很难鉴定出自闭症样行为（7,8）。在这里我们报告基于慢病毒的转基因食蟹猕猴（猕猴）在大脑中表达人类MeCP2表现出自闭症样的行为，并显示转基因的种系传递。通过蛋白质印迹和转基因猴子脑组织的免疫染色证实了MECP2转基因的表达。转基因的基因组整合位点通过基于深度测序的方法进行了表征。与野生型猴子相比，MECP2转基因猴子表现出更高的重复循环运动频率和增加的应激反应（通过威胁相关的焦虑和防御测试来衡量）（9）。转基因猴子在同一组中与野生型猴子的互动较少，并且在社交互动测试中与其他转基因猴子配对时互动时间也缩短了。转基因猴子的认知功能在威斯康星州的通用测试仪器中基本上是正常的，尽管有些表现出刻板的认知行为迹象。值得注意的是，我们成功地通过胞浆内单精子注射一只F-0转基因猴的精子成功产生了5只MECP2转基因猴的F-1后代，显示出F-1后代中几种MECP2转基因的种系传播和孟德尔分离。而且，与相似年龄的野生型猴子相比，成对测试的F-1转基因猴子还表现出减少的社交互动。总之，这些结果表明使用基因工程非人类灵长类动物研究脑部疾病的可行性和可靠性。

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  • 来源
    《Nature》 |2016年第7588期|98-102|共5页
  • 作者

    Liu Zhen; Li Xiao; Zhang Jun-Tao; Cai Yi-Jun; Cheng Tian-Lin; Cheng Cheng; Wang Yan; Zhang Chen-Chen; Nie Yan-Hong; Chen Zhi-Fang; Bian Wen-Jie; Zhang Ling; Xiao Jianqiu; Lu Bin; Zhang Yue-Fang; Zhang Xiao-Di; Sang Xiao; Wu Jia-Jia; Xu Xiu; Xiong Zhi-Qi; Zhang Feng; Yu Xiang; Gong Neng; Zhou Wen-Hao; Sun Qiang; Qiu Zilong;

  • 作者单位

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Fudan Univ, State Key Lab Genet Engn, Shanghai 200438, Peoples R China|Fudan Univ, Minist Educ, Key Lab Contemporary Anthropol, Collaborat Innovat Ctr Genet & Dev,Sch Life Sci, Shanghai 200438, Peoples R China;

    Fudan Univ, State Key Lab Genet Engn, Shanghai 200438, Peoples R China|Fudan Univ, Minist Educ, Key Lab Contemporary Anthropol, Collaborat Innovat Ctr Genet & Dev,Sch Life Sci, Shanghai 200438, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Fudan Univ, Childrens Hosp, Dept Child Healthcare, Shanghai 201102, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Fudan Univ, State Key Lab Genet Engn, Shanghai 200438, Peoples R China|Fudan Univ, Minist Educ, Key Lab Contemporary Anthropol, Collaborat Innovat Ctr Genet & Dev,Sch Life Sci, Shanghai 200438, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Fudan Univ, Childrens Hosp, Dept Neonatol, Shanghai 201102, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

    Chinese Acad Sci, CAS Key Lab Primate Neurobiol, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci,State Key Lab Neurosci,Shanghai Ins, 320 Yue Yang Rd, Shanghai 200031, Peoples R China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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