Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

Yongchang Chen; Juehua Yu; Yuyu Niu; Dongdong Qin; Hailiang Liu; Gang Li; Yingzhou Hu; Jiaojian Wang; Yi Lu; Yu Kang; Yong Jiang; Kunhua Wu; Siguang Li; Jingkuan Wei; Jing He; Junbang Wang; Xiaojing Liu; Yuping Luo; Chenyang Si; Raoxian Bai; Kunshan Zhang; Jie Liu; Shaoyong Huang; Zhenzhen Chen; Shuang Wang; Xiaoying Chen; Xinhua Bao; Qingping Zhang; Fuxing Li; Rui Geng; Aibin Liang; Dinggang Shen; Tianzi Jiang; Xintian Hu; Yuanye Ma; Weizhi Ji; Yi Eve Sun

doi:10.1016/j.cell.2017.04.035

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

Cell. 2017 May 18;169(5):945-955.e10. doi: 10.1016/j.cell.2017.04.035.

Authors

Yongchang Chen¹, Juehua Yu², Yuyu Niu³, Dongdong Qin⁴, Hailiang Liu², Gang Li⁵, Yingzhou Hu⁴, Jiaojian Wang⁶, Yi Lu⁷, Yu Kang³, Yong Jiang⁸, Kunhua Wu⁸, Siguang Li², Jingkuan Wei⁹, Jing He⁹, Junbang Wang², Xiaojing Liu², Yuping Luo², Chenyang Si³, Raoxian Bai⁹, Kunshan Zhang², Jie Liu², Shaoyong Huang⁹, Zhenzhen Chen⁹, Shuang Wang⁹, Xiaoying Chen², Xinhua Bao¹⁰, Qingping Zhang¹⁰, Fuxing Li², Rui Geng², Aibin Liang², Dinggang Shen⁵, Tianzi Jiang¹¹, Xintian Hu⁴, Yuanye Ma⁹, Weizhi Ji¹², Yi Eve Sun¹³

Affiliations

¹ Yunnan Key Laboratory of Primate Biomedicine Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China; Yunnan Provincial Academy of Science and Technology, Kunming 650051, China; Kunming Enovate Institute of Bioscience, Kunming 650000, China. Electronic address: chenyc@lpbr.cn.
² Translational Stem Cell Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
³ Yunnan Key Laboratory of Primate Biomedicine Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China; Yunnan Provincial Academy of Science and Technology, Kunming 650051, China; Kunming Enovate Institute of Bioscience, Kunming 650000, China.
⁴ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
⁵ Department of Radiology and BRIC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Key Laboratory for NeuroInformation of the Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 625014, China.
⁷ Department of Medical Imaging, the First Affiliated Hospital, Kunming Medical University, Kunming 650032, China.
⁸ The First People's Hospital of Yunnan Province and The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, China.
⁹ Yunnan Key Laboratory of Primate Biomedicine Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China; Yunnan Provincial Academy of Science and Technology, Kunming 650051, China.
¹⁰ Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
¹¹ Key Laboratory for NeuroInformation of the Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 625014, China; National Laboratory of Pattern Recognition, Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.
¹² Yunnan Key Laboratory of Primate Biomedicine Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China; Yunnan Provincial Academy of Science and Technology, Kunming 650051, China; Kunming Enovate Institute of Bioscience, Kunming 650000, China. Electronic address: wji@lpbr.cn.
¹³ Translational Stem Cell Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Department of Psychiatry and Biobehavioral Sciences, UCLA Medical School, Los Angeles, CA 90095, USA. Electronic address: ysun@mednet.ucla.edu.

Abstract

Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT.

Keywords: MECP2; Rett syndrome; disease models; gene editing; male embryonic lethal; neurodevelopmental disorder; non-human primate.

MeSH terms

Animals
Brain / physiology
Chromosomes, Human, X
Circadian Rhythm
Disease Models, Animal
Electrocardiography
Female
Gene Editing
Humans
Macaca fascicularis
Magnetic Resonance Imaging
Male
Methyl-CpG-Binding Protein 2 / genetics*
Mutation
Pain
Rett Syndrome / genetics*
Rett Syndrome / physiopathology
Sleep
Transcription Activator-Like Effector Nucleases / metabolism
Transcriptome

Substances

Methyl-CpG-Binding Protein 2
Transcription Activator-Like Effector Nucleases

Abstract

MeSH terms

Substances

Grants and funding