Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

被引：179

作者：

Chen, Yongchang ^{[1
,3
,14
]}

Yu, Juehua ^{[2
]}

Niu, Yuyu ^{[1
,3
,14
]}

Qin, Dongdong ^{[5
]}

Liu, Hailiang ^{[2
]}

Li, Gang ^{[6
,7
]}

Hu, Yingzhou ^{[5
]}

Wang, Jiaojian ^{[8
]}

Lu, Yi ^{[9
]}

Kang, Yu ^{[1
,3
,14
]}

Jiang, Yong ^{[10
,11
]}

Wu, Kunhua ^{[10
,11
]}

Li, Siguang ^{[2
]}

Wei, Jingkuan ^{[1
,3
]}

He, Jing ^{[1
,3
]}

Wang, Junbang ^{[2
]}

Liu, Xiaojing ^{[2
]}

Luo, Yuping ^{[2
]}

Si, Chenyang ^{[1
,3
,14
]}

Bai, Raoxian ^{[1
,3
]}

Zhang, Kunshan ^{[2
]}

Liu, Jie ^{[2
]}

Huang, Shaoyong ^{[1
,3
]}

Chen, Zhenzhen ^{[1
,3
]}

Wang, Shuang ^{[1
,3
]}

Chen, Xiaoying ^{[2
]}

Bao, Xinhua ^{[12
]}

Zhang, Qingping ^{[12
]}

Li, Fuxing ^{[2
]}

Geng, Rui ^{[2
]}

Liang, Aibin ^{[2
]}

Shen, Dinggang ^{[6
,7
]}

Jiang, Tianzi ^{[8
,13
]}

Hu, Xintian ^{[5
]}

Ma, Yuanye ^{[1
,3
]}

Ji, Weizhi ^{[1
,3
,14
]}

Sun, Yi Eve ^{[2
,4
]}

机构：

[1] Kunming Univ Sci & Technol, Inst Primate Translat Med, Yunnan Key Lab Primate Biomed Res, Kunming 650500, Peoples R China

[2] Tongji Univ, Sch Med, Tongji Hosp, Translat Stem Cell Res Ctr, Shanghai 200065, Peoples R China

[3] Yunnan Prov Acad Sci & Technol, Kunming 650051, Peoples R China

[4] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA

[5] Chinese Acad Sci, Kunming Inst Zool, Chinese Acad Sci & Yunnan Prov, Key Lab Anim Models & Human Dis Mech, Kunming 650223, Peoples R China

[6] Univ North Carolina Chapel Hill, Dept Radiol, Chapel Hill, NC 27599 USA

[7] Univ North Carolina Chapel Hill, BRIC, Chapel Hill, NC 27599 USA

[8] Univ Elect Sci & Technol China, Sch Life Sci & Technol, Minist Educ, Key Lab NeuroInformat, Chengdu 625014, Peoples R China

[9] Kunming Med Univ, Affiliated Hosp 1, Dept Med Imaging, Kunming 650032, Peoples R China

[10] Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Kunming 650032, Peoples R China

[11] Kunming Univ Sci & Technol, Affiliated Hosp, Kunming 650032, Peoples R China

[12] Peking Univ, Hosp 1, Dept Pediat, Beijing 100034, Peoples R China

[13] Chinese Acad Sci, Inst Automat, Brainnetome Ctr, Natl Lab Pattern Recognit, Beijing 100190, Peoples R China

[14] Kunming Enovate Inst Biosci, Kunming 650000, Peoples R China

来源：

CELL | 2017年 / 169卷 / 05期

关键词：

CPG-BINDING PROTEIN-2; NETWORK ANALYSIS; MICE; PRIMATES; AUTISM; GIRLS; ABNORMALITIES; NEUROANATOMY; DEFICIENCY; REGRESSION;

D O I：

10.1016/j.cell.2017.04.035

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：945 / +

页数：21

共 44 条

[1] Rapid Determination of the Thermal Nociceptive Threshold in Diabetic Rats [J].

Alshahrani, Saeed ;

Fernandez-Conti, Filipe ;

Araujo, Amanda ;

DiFulvio, Mauricio .

JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, 2012, (63)

[2] OBSERVATIONAL STUDY OF BEHAVIOR - SAMPLING METHODS [J].

ALTMANN, J .

BEHAVIOUR, 1974, 49 (3-4) :227-267

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

Amir, RE ;

Van den Veyver, IB ;

Wan, M ;

Tran, CQ ;

Francke, U ;

Zoghbi, HY .

NATURE GENETICS, 1999, 23 (02) :185-188

[4] Brains, Genes, and Primates [J].

Belmonte, Juan Carlos Izpisua ;

Callaway, Edward M. ;

Churchland, Patricia ;

Caddick, Sarah J. ;

Feng, Guoping ;

Homanics, Gregg E. ;

Lee, Kuo-Fen ;

Leopold, David A. ;

Miller, Cory T. ;

Mitchell, Jude F. ;

Mitalipov, Shoukhrat ;

Moutri, Alysson R. ;

Movshon, J. Anthony ;

Okano, Hideyuki ;

Reynolds, John H. ;

Ringach, Dario ;

Sejnowski, Terrence J. ;

Silva, Afonso C. ;

Strick, Peter L. ;

Wu, Jun ;

Zhang, Feng .

NEURON, 2015, 86 (03) :617-631

[5] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[6]

Bjure J, 1997, EUR CHILD ADOLES PSY, V6, P64

[7] Selective cerebral volume reduction in Rett syndrome: A multiple-approach MR imaging study [J].

Carter, J. C. ;

Lanham, D. C. ;

Pham, D. ;

Bibat, G. ;

Naidu, S. ;

Kaufmann, W. E. .

AMERICAN JOURNAL OF NEURORADIOLOGY, 2008, 29 (03) :436-441

[8] Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice [J].

Chen, RZ ;

Akbarian, S ;

Tudor, M ;

Jaenisch, R .

NATURE GENETICS, 2001, 27 (03) :327-331

[9] Social Preferences in Rett Syndrome [J].

Djukic, Aleksandra ;

McDermott, Maria Valicenti .

PEDIATRIC NEUROLOGY, 2012, 46 (04) :240-242

[10] Rett syndrome: Of girls and mice - Lessons for regression in autism [J].

Glaze, DG .

MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS, 2004, 10 (02) :154-158

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