Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing1,2,3,4. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes5. Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders6. 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 overexpression7,8. 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 test9. 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 F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from one F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 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.
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Gene Expression Omnibus
The raw sequence and processed data have been submitted to the NCBI Gene Expression Ominbus (GEO) under accession number GSE57974.
We thank M.-m. Poo for comments on the manuscript, Y.-Z. Li, Y.-Z. Lu, F. Liu and X. Zhou for maintaining monkey colony, W. Lu, X.-H. Guo and Y. F. Zhou of Fudan Children’s Hospital for assistance in mass spectrometry and electroencephalogram, D. Chen and B. Zhang of Novel Bioinformatics for RNA-seq data analysis, and C.-H. Li of Shanghai Geneskies Company for analysis of genomic integration sites. This work was supported by CAS Strategic Priority Research Program (XDB02050400), the MoST 973 Program (2011CBA00400), NSFC grants (91432111, 91232712 and 81527901), National Key Technology R&D Program of China 2014BAI03B00, Shanghai City Committee of Science and Technology Project 14140900100.
Extended data figures
Extended data tables
This video shows the representative normal motor behaviours for monkeys we examined.
This video shows the typical repetitive motor behaviours for four F0 TG monkeys out of eight F0 TG monkeys we examined.
This video shows the representative social interaction behaviours of monkeys, such as sitting together, in natural community.
This video shows the typical social behaviour, sitting together, in pairing experiments.
This video shows the example of learned behaviours for W09 out of five WT monkeys we examined.
This video shows the example of stereotypic responses of F0 TG monkeys (T09) out of seven F0 TG monkeys we examined.
About this article
Journal of Human Genetics (2018)