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

Published on Dec 20, 2015in Human Molecular Genetics 4.90
· DOI :10.1093/hmg/ddv425
Yu Kang8
Estimated H-index: 8
(Kunming University),
Bo Zheng8
Estimated H-index: 8
(Nanjing Medical University)
+ 13 AuthorsXingxu Huang7
Estimated H-index: 7
(ShanghaiTech University)
Abstract
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/β-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.
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  • Citations (36)
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References35
Newest
Andrzej Slominski74
Estimated H-index: 74
(UT: University of Tennessee),
Wei Li37
Estimated H-index: 37
(UT: University of Tennessee)
+ 4 AuthorsRobert C. Tuckey39
Estimated H-index: 39
(UWA: University of Western Australia)
Abstract CYP11A1, found only in vertebrates, catalyzes the first step of steroidogenesis where cholesterol is converted to pregnenolone. The purified enzyme, also converts desmosterol and plant sterols including campesterol and β-sitosterol, to pregnenolone. Studies, initially with purified enzyme, reveal that 7-dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates th...
86 Citations Source Cite
Published on Feb 1, 2015in Cell Research 15.39
Yongchang Chen11
Estimated H-index: 11
,
Yiqiang Cui9
Estimated H-index: 9
+ 9 AuthorsWeizhi Ji23
Estimated H-index: 23
17 Citations Source Cite
Published on Dec 1, 2014in FEBS Journal 4.53
Yuanwu Ma6
Estimated H-index: 6
(Academy of Medical Sciences, United Kingdom),
Lianfeng Zhang6
Estimated H-index: 6
(Academy of Medical Sciences, United Kingdom),
Xingxu Huang5
Estimated H-index: 5
(National Resource Center)
Clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein (Cas)9-mediated genome modification enables us to edit the genomes of a variety of organisms rapidly and efficiently. The advantages of the CRISPR–Cas9 system have made it an increasingly popular genetic engineering tool for biological and therapeutic applications. Moreover, CRISPR–Cas9 has been employed to recruit functional domains that repress/activate gene expression or label specific genomic loci in...
44 Citations Source Cite
Published on Feb 1, 2014in Cell 31.40
Yuyu Niu15
Estimated H-index: 15
,
Bin Shen14
Estimated H-index: 14
(National Resource Center)
+ 25 AuthorsWei Li41
Estimated H-index: 41
(CAS: Chinese Academy of Sciences)
Summary Monkeys serve as important model species for studying human diseases and developing therapeutic strategies, yet the application of monkeys in biomedical researches has been significantly hindered by the difficulties in producing animals genetically modified at the desired target sites. Here, we first applied the CRISPR/Cas9 system, a versatile tool for editing the genes of different organisms, to target monkey genomes. By coinjection of Cas9 mRNA and sgRNAs into one-cell-stage embryos, w...
584 Citations Source Cite
Published on Feb 1, 2014in Proteomics 3.53
Bo Zheng8
Estimated H-index: 8
(Nanjing Medical University),
Quan Zhou6
Estimated H-index: 6
(Nanjing Medical University)
+ 7 AuthorsXiaoyan Huang11
Estimated H-index: 11
(Nanjing Medical University)
Initiation of the first wave of spermatogenesis in the neonatal mouse testis is characterized by differentiation of a transient population of germ cells called gonocytes in the center of the seminiferous tubules. After resuming mitotic activity, gonocytes relocate on the basement membrane, giving rise to spermatogonial stem cells (SSCs). These processes begin from birth in mice, and differentiated type A spermatogonia first appear by day 6 postpartum. During these processes, Sertoli cells within...
13 Citations Source Cite
Published on Oct 1, 2013in Nature Methods 26.92
Prashant Mali29
Estimated H-index: 29
,
Kevin M. Esvelt16
Estimated H-index: 16
,
George M Church G M135
Estimated H-index: 135
This Perspective describes current and prospective advances in genome engineering made possible with the CRISPR-Cas9 system.
727 Citations Source Cite
Published on May 1, 2013in Experimental Cell Research 3.31
Marco Reis3
Estimated H-index: 3
(Goethe University Frankfurt),
Stefan Liebner31
Estimated H-index: 31
(Goethe University Frankfurt)
Abstract The development of the vascular system requires orchestrated activities of various molecular pathways to assure the formation of a hierarchically branched tubular network. Furthermore, endothelial cell (EC) populations are heterogeneous to meet organ-specific requirements in the mature vasculature. This developmental scheme is probably best represented by the acquisition and maintenance of unique barrier properties known as the blood–brain barrier (BBB) in microvessels of the central ne...
86 Citations Source Cite
Published on Jan 1, 2013in Ilar Journal 2.62
Anthony W. S. Chan1
Estimated H-index: 1
The growing interest of modeling human diseases using genetically modified (transgenic) nonhuman primates (NHPs) is a direct result of NHPs (rhesus macaque, etc.) close relation to humans. NHPs share similar developmental paths with humans in their anatomy, physiology, genetics, and neural functions; and in their cognition, emotion, and social behavior. The NHP model within biomedical research has played an important role in the development of vaccines, assisted reproductive technologies, and ne...
32 Citations Source Cite
Published on Aug 1, 2012in Journal of Assisted Reproduction and Genetics 2.79
Donata Ponikwicka-Tyszko6
Estimated H-index: 6
(PAN: Polish Academy of Sciences),
Malgorzata Kotula-Balak16
Estimated H-index: 16
(Jagiellonian University)
+ 2 AuthorsSlawomir Wolczynski26
Estimated H-index: 26
(PAN: Polish Academy of Sciences)
Hypogonadotropic hypogonadism (HH) associated with adrenal hypoplasia congenita (AHC) is a very rare syndrome caused by mutation of DAX1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome) [19]. The DAX1 is located on the chromosome X (Xp21.3–21.2) and contains two exons. It encodes a 470-amino acid protein which belongs to the nuclear hormone receptor superfamily (called DAX1). DAX1 is expressed in the adrenal cortex, pituitary and hypothalamus, gona...
9 Citations Source Cite
Published on Mar 1, 2012in Cell 31.40
Lukas E. Dow23
Estimated H-index: 23
(MSK: Memorial Sloan Kettering Cancer Center),
Scott W. Lowe114
Estimated H-index: 114
(MSK: Memorial Sloan Kettering Cancer Center)
Analyses of the human genome have proven extremely successful in identifying changes that contribute to human disease. Genetically engineered mice provide a powerful tool to analyze these changes, although they are slow and costly and do not always recapitulate human biology. Recent advances in genomic technologies, rodent-modeling approaches, and the production of patient-derived reprogrammed cell lines now provide a plethora of complementary systems to study disease states and test new therapi...
56 Citations Source Cite
Cited By36
Newest
Published on Jan 15, 2019in BMC Biotechnology 2.60
Chu Chu1
Estimated H-index: 1
(Kunming University of Science and Technology),
Zhaohui Yang1
Estimated H-index: 1
(Kunming University of Science and Technology)
+ 7 AuthorsYuyu Niu15
Estimated H-index: 15
(Kunming University of Science and Technology)
Background Non-human primate (NHP) models can closely mimic human physiological functions and are therefore highly valuable in biomedical research. Genome editing is now developing rapidly due to the precision and efficiency offered by engineered site-specific endonuclease-based systems, such as transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) system. It has been demonst...
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Published on Mar 28, 2019in The FASEB Journal 5.59
Jun Yu1
Estimated H-index: 1
(Jiangsu University),
Xiaojin Luan (Jiangsu University)+ 16 AuthorsWanyin Chen1
Estimated H-index: 1
(Jiangsu University)
The ribonucleoprotein (RNP) spliceosome machinery triggers the precursor RNA splicing process in eukaryotes. Major spliceosome defects are implicated in male infertility; however, the underlying mechanistic links between the spliceosome and the ribosome in Drosophila testes remains largely unresolved. Small ribonucleoprotein particle protein SmD3 (SmD3) is a novel germline stem cell (GSC) regulatory gene identified in our previous screen of Drosophila testes. In the present study, using genetic ...
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Published on Mar 14, 2019in Biology of Reproduction 3.18
Yasunari Seita3
Estimated H-index: 3
(Shiga University of Medical Science),
Tomoyuki Tsukiyama2
Estimated H-index: 2
(Kyoto University)
+ 10 AuthorsHiroyuki Miyoshi47
Estimated H-index: 47
(Keio: Keio University)
1 Citations Source Cite
Published on Jan 31, 2019in National Science Review 9.41
Jianguo Zhao (CAS: Chinese Academy of Sciences), Liangxue Lai (Guangzhou Institutes of Biomedicine and Health)+ 1 AuthorsQi Zhou51
Estimated H-index: 51
(CAS: Chinese Academy of Sciences)
Source Cite
Published on Mar 1, 2019
Lucie Chansel-Debordeaux1
Estimated H-index: 1
,
Erwan Bezard66
Estimated H-index: 66
Source Cite
Published on Jan 1, 2019
Nicole S. Lee2
Estimated H-index: 2
,
Annaliese K. Beery16
Estimated H-index: 16
1 Citations Source Cite
Published on Dec 1, 2018in Seminars in Perinatology 2.88
Fani Memi4
Estimated H-index: 4
(UCL: University College London),
Aglaia Ntokou1
Estimated H-index: 1
(Yale University),
Irinna Papangeli7
Estimated H-index: 7
(Yale University)
Abstract Gene therapy carries the potential to treat more than 10,000 human monogenic diseases and benefit an even greater number of complex polygenic conditions. The repurposing of CRISPR/Cas9, an ancient bacterial immune defense system, into a gene-editing technology has armed researchers with a revolutionary tool for gene therapy. However, as the breadth of research and clinical applications of this technology continues to expand, outstanding technical challenges and ethical considerations wi...
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Published on Oct 1, 2018in Biochemical and Biophysical Research Communications 2.56
Cong Shen2
Estimated H-index: 2
(Nanjing Medical University),
Ke Zhang (Nanjing Medical University)+ 12 AuthorsHongbo Cheng (Nanjing Medical University)
Abstract Stromal interaction molecule 1 (STIM1) is a transmembrane endoplasmic reticulum protein, and it serves as a Ca 2+ sensor and activator of store-operated Ca 2+ entry (SOCE). We have previously identified STIM1 in the proteome profile of mice neonatal testes, revealing STIM1 to be associated with neonatal testicular development. Here, to further explore the location and function of STIM1 in mice testes, we studied the effect of Stim1 gene knockdown on neonatal testicular development by te...
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Published on Sep 18, 2018in Genetics research international
Bilal Ahmad Lone (South Asian University), Shibendra Kumar Lal Karna1
Estimated H-index: 1
(South Asian University)
+ 2 AuthorsYuba Raj Pokharel1
Estimated H-index: 1
(South Asian University)
Microbes use diverse defence strategies that allow them to withstand exposure to a variety of genome invaders such as bacteriophages and plasmids. One such defence strategy is the use of RNA guided endonuclease called CRISPR-associated (Cas) 9 protein. The Cas9 protein, derived from type II CRISPR/Cas system, has been adapted as a versatile tool for genome targeting and engineering due to its simplicity and high efficiency over the earlier tools such as ZFNs and TALENs. With recent advancements,...
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