CRISPR/Cas9-mediated Dax1 knockout in the monkey recapitulates human AHC-HH

doi:10.1093/hmg/ddv425

	CRISPR/Cas9-mediated Dax1 knockout in the monkey recapitulates human AHC-HH
	Kang, Yu 1,2,3; Zheng, Bo 4; Shen, Bin 4; Chen, Yongchang 1,2,3; Wang, Lei 4; Wang, Jianying 4; Niu, Yuyu 1,2,3; Cui, Yiqiang 4; Zhou, Jiankui5,6 ; Wang, Hong 1,2,3; Guo, Xuejiang 4; Hu, Bian 5,6; Zhou, Qi 7; Sha, Jiahao 4; Ji, Weizhi 1,2,3; Huang, Xingxu5,6
	2015-12-20
发表期刊	HUMAN MOLECULAR GENETICS
ISSN	0964-6906
卷号	24 期号:25 页码:7255-7264
发表状态	已发表
DOI	10.1093/hmg/ddv425
摘要	Mutations in the DAX1 locus cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH), which manifest with primary adrenal insufficiency and incomplete or absent sexual maturation, respectively. The associated defects in spermatogenesis can range from spermatogenic arrest to Sertoli cell only syndrome. Conclusions from Dax1 knockout mouse models provide only limited insight into AHC/HH disease mechanisms, because mouse models exhibit more extensive abnormalities in testicular development, including disorganized and incompletely formed testis cords with decreased number of peritubular myoid cells and male-to-female sex reversal. We previously reported successful clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated genome targeting in cynomolgus monkeys. Here, we describe a male fetal monkey in which targeted genome editing using CRISPR/Cas9 produced Dax1-null mutations in most somatic tissues and in the gonads. This DAX1-deficient monkey displayed defects in adrenal gland development and abnormal testis architecture with small cords, expanded blood vessels and extensive fibrosis. Sertoli cell formation was not affected. This phenotype strongly resembles findings in human patients with AHC-HH caused by mutations in DAX1. We further detected upregulation of Wnt/beta-catenin-VEGF signaling in the fetal Dax1-deficient testis, suggesting abnormal activation of signaling pathways in the absence of DAX1 as one mechanism of AHC-HH. Our study reveals novel insight into the role of DAX1 in HH and provides proof-of-principle for the generation of monkey models of human disease via CRISPR/Cas9-mediated gene targeting.
收录类别	SCI
语种	英语
资助项目	National High Technology Research and Development Program of China[2012AA020701]
WOS研究方向	Biochemistry & Molecular Biology ; Genetics & Heredity
WOS类目	Biochemistry & Molecular Biology ; Genetics & Heredity
WOS记录号	WOS:000368373600009
出版者	OXFORD UNIV PRESS
WOS关键词	ADRENAL HYPOPLASIA CONGENITA ; FACTOR-I NR5A1 ; HYPOGONADOTROPIC HYPOGONADISM ; PHENOTYPIC SPECTRUM ; GENE ; EXPRESSION ; DIFFERENTIATION ; INITIATION ; MUTATION ; FAILURE
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2070
专题	生命科学与技术学院_PI研究组_黄行许组
通讯作者	Huang, Xingxu
作者单位	1.Kunming Univ Sci & Technol, Fac Life Sci & Technol, Inst Primate Translat Med Res, Kunming 650500, Peoples R China 2.Yunnan Key Lab Primate Biomed Res, Kunming 650500, Peoples R China 3.Natl Engn Res Ctr Biomed & Anim Sci, Kunming 650500, Peoples R China 4.Nanjing Med Univ, Dept Histol & Embryol, State Key Lab Reprod Med, Nanjing 210029, Jiangsu, Peoples R China 5.Nanjing Univ, Natl Resource Ctr Mutant Mice, Model Anim Res Ctr, MOE Key Lab Model Anim Dis Study, Nanjing 210061, Jiangsu, Peoples R China 6.ShanghaiTech Univ, Sch Life Sci & Technol, Pudong New Area, Shanghai 201210, Peoples R China 7.Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, Beijing 100101, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Kang, Yu,Zheng, Bo,Shen, Bin,et al. CRISPR/Cas9-mediated Dax1 knockout in the monkey recapitulates human AHC-HH[J]. HUMAN MOLECULAR GENETICS,2015,24(25):7255-7264.
APA	Kang, Yu.,Zheng, Bo.,Shen, Bin.,Chen, Yongchang.,Wang, Lei.,...&Huang, Xingxu.(2015).CRISPR/Cas9-mediated Dax1 knockout in the monkey recapitulates human AHC-HH.HUMAN MOLECULAR GENETICS,24(25),7255-7264.
MLA	Kang, Yu,et al."CRISPR/Cas9-mediated Dax1 knockout in the monkey recapitulates human AHC-HH".HUMAN MOLECULAR GENETICS 24.25(2015):7255-7264.