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

作　　者：Qiong Ke Weiqiang Li Xingqiang Lai Hong Chen Lihua Huang Zhuang Kang Kai Li Jie Ren Xiaofeng Lin Haiqing Zheng Weijun Huang Yunhan Ma Dongdong Xu Zheng Chen Xinming Song Xinyi Lin Min Zhuang Tao Wang Fengfeng Zhuang Jianzhong Xi Frank Fuxiang Mao Huimin Xia Bruce T Lahn Qi Zhou Shihua Yang Andy Peng Xiang 

机构地区：[1]Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510623, China [2]Center 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 [3]Department of Biology, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou 510080, China [4]Guangdong Key Laboratory of Reproductive Medicine, Guangzhou 510080, China [5]Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou 510080, China [6]Department of Radiology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510632, China [7]Department of Ultrasound, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510632, China [8]Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China [9]Department of Rehabilitation Medicine Science, the Third Ajfiliated Hospital of Sun Yat-sen University, Guangzhou 510632, China [10]College of Veterinary Medicine, Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, South China Agricultural University, Guangzhou 510642, China [11]Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China [12]School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China [13]Beijing ViewSolid Biotechnology, Beoing 100034, China [14]Department of Biomedical Engineering, College of Engineering, Peking University, Yannan Yuan 60, Beijing 100871, China [15]State Key Laboratory of Ophthalmology, Zhong Shan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [16]Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA [17]State Key Laboratory of Stem cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

出　　处：《Cell Research》2016年第9期1048-1061,共14页细胞研究（英文版）

基　　金：Acknowledgments This work was supported by the National Basic Research Program of China （2012CBA01302）, the National Natural Science Foundation of China （81425016, 31301219 and 81570593）, the Fundamental Research Funds for the Central Universities （15ykjc01c）, PhD Programs Foundation of Ministry of Education of China （20130171120061）, the Key Scientific and Technological Projects of Guangdong Province （2014B020226002, 2014B020228003, 2014B020225007, 2015B020228002 and 2016B030229002）, Key Scientific and Technological Program of Guangzhou City （201400000003-3, 201508020262, 201300000089 and 2010U 1-E00551）, Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme （GDUPS, 2013） and Pearl River S＆T Nova Program of Guangzhou （2014J2200037）.

摘　　要：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. Micro- cephalin 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 （Macacafascicularis） 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.

关 键 词：MCPH1 MICROCEPHALY TALEN gene mutant cynomolgus monkey 

分 类 号：Q[生物学]