Volume 26, No 9, Sep 2016

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 26 Issue 9, September 2016: 1048-1061

ORIGINAL ARTICLES

TALEN-based generation of a cynomolgus monkey disease model for human microcephaly

Qiong Ke^1,2,3,4,*, Weiqiang Li^1,2,4,5,*, Xingqiang Lai^2,*, Hong Chen², Lihua Huang¹, Zhuang Kang⁶, Kai Li⁷, Jie Ren⁷, Xiaofeng Lin⁸, Haiqing Zheng⁹, Weijun Huang², Yunhan Ma¹⁰, Dongdong Xu¹⁰, Zheng Chen¹¹, Xinming Song¹¹, Xinyi Lin1¹, Min Zhuang1², Tao Wang^2,5, Fengfeng Zhuang¹³, Jianzhong Xi¹⁴, Frank Fuxiang Mao¹⁵, Huimin Xia¹, Bruce T Lahn1⁶, Qi Zhou1⁷, Shihua Yang¹⁰ and Andy Peng Xiang^1,2,4,5

¹Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510623, China
²Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, China
³Department of Biology, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou 510080, China
⁴Guangdong Key Laboratory of Reproductive Medicine, Guangzhou 510080, China
⁵Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou 510080, China
⁶Department of Radiology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510632, China
⁷Department of Ultrasound, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510632, China
⁸Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
⁹Department of Rehabilitation Medicine Science, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510632, China
¹⁰College of Veterinary Medicine, Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, South China Agricultural University, Guangzhou 510642, China
¹¹Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
¹²School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
¹³Beijing ViewSolid Biotechnology, Beijing 100034, China
¹⁴Department of Biomedical Engineering, College of Engineering, Peking University, Yannan Yuan 60, Beijing 100871, China
¹⁵State Key Laboratory of Ophthalmology, Zhong Shan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
¹⁶Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
¹⁷State Key Laboratory of Stem cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China Correspondence: Andy Peng Xiang, E-mail: xiangp@mail.sysu.edu.cn; Shihua Yang, E-mail: yangsh@scau.edu.cn; Qi Zhou,(qzhou@ioz.ac.cn)

Gene editing in non-human primates may lead to valuable models for exploring the etiologies and therapeutic strategies of genetically based neurological disorders in humans. However, a monkey model of neurological disorders that closely mimics pathological and behavioral deficits in humans has not yet been successfully generated. Microcephalin 1 (MCPH1) is implicated in the evolution of the human brain, and MCPH1 mutation causes microcephaly accompanied by mental retardation. Here we generated a cynomolgus monkey (Macaca fascicularis) carrying biallelic MCPH1 mutations using transcription activator-like effector nucleases. The monkey recapitulated most of the important clinical features observed in patients, including marked reductions in head circumference, premature chromosome condensation (PCC), hypoplasia of the corpus callosum and upper limb spasticity. Moreover, overexpression of MCPH1 in mutated dermal fibroblasts rescued the PCC syndrome. This monkey model may help us elucidate the role of MCPH1 in the pathogenesis of human microcephaly and better understand the function of this protein in the evolution of primate brain size.

10.1038/cr.2016.93

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