Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2

被引：256

作者：

Liu, Zhen ^{[1
]}

Li, Xiao ^{[1
]}

Zhang, Jun-Tao ^{[1
]}

Cai, Yi-Jun ^{[1
]}

Cheng, Tian-Lin ^{[1
]}

Cheng, Cheng ^{[1
]}

Wang, Yan ^{[1
]}

Zhang, Chen-Chen ^{[1
]}

Nie, Yan-Hong ^{[1
]}

Chen, Zhi-Fang ^{[1
]}

Bian, Wen-Jie ^{[1
]}

Zhang, Ling ^{[2
,3
]}

Xiao, Jianqiu ^{[2
,3
]}

Lu, Bin ^{[1
]}

Zhang, Yue-Fang ^{[1
]}

Zhang, Xiao-Di ^{[1
]}

Sang, Xiao ^{[1
]}

Wu, Jia-Jia ^{[1
]}

Xu, Xiu ^{[4
]}

Xiong, Zhi-Qi ^{[1
]}

Zhang, Feng ^{[2
,3
]}

Yu, Xiang ^{[1
]}

Gong, Neng ^{[1
]}

Zhou, Wen-Hao ^{[5
]}

Sun, Qiang ^{[1
]}

Qiu, Zilong ^{[1
]}

机构：

[1] 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

[2] Fudan Univ, State Key Lab Genet Engn, Shanghai 200438, Peoples R China

[3] Fudan Univ, Minist Educ, Key Lab Contemporary Anthropol, Collaborat Innovat Ctr Genet & Dev,Sch Life Sci, Shanghai 200438, Peoples R China

[4] Fudan Univ, Childrens Hosp, Dept Child Healthcare, Shanghai 201102, Peoples R China

[5] Fudan Univ, Childrens Hosp, Dept Neonatol, Shanghai 201102, Peoples R China

来源：

NATURE | 2016年 / 530卷 / 7588期

关键词：

MACAQUE MACACA-FASCICULARIS; TRANSCRIPTIONAL REPRESSOR; NONHUMAN-PRIMATES; RHESUS-MONKEYS; GENERATION; CYNOMOLGUS; AMYGDALA; INFANT; DISEASE; ANXIETY;

D O I：

10.1038/nature16533

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：98 / +

页数：18

共 45 条

[1] Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 [J].