CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling

被引：1505

作者：

Platt, Randall J. ^{[1
,2
,3
,4
]}

Chen, Sidi ^{[5
,6
]}

Zhou, Yang ^{[2
,3
]}

Yim, Michael J. ^{[1
,2
,3
,4
]}

Swiech, Lukasz ^{[1
,2
,3
,4
]}

Kempton, Hannah R. ^{[1
,2
,4
]}

Dahlman, James E. ^{[5
,7
,8
]}

Parnas, Oren ^{[1
]}

Eisenhaure, Thomas M. ^{[1
,11
]}

Jovanovic, Marko ^{[1
]}

Graham, Daniel B. ^{[1
]}

Jhunjhunwala, Siddharth ^{[5
]}

Heidenreich, Matthias ^{[1
,2
,3
,4
]}

Xavier, Ramnik J. ^{[1
]}

Langer, Robert ^{[5
,7
,8
,9
]}

Anderson, Daniel G. ^{[5
,7
,8
,9
]}

Hacohen, Nir ^{[1
,10
,11
]}

Regev, Aviv ^{[1
,6
,12
]}

Feng, Guoping ^{[1
,2
,3
,13
]}

Sharp, Phillip A. ^{[5
,6
]}

Zhang, Feng ^{[1
,2
,3
,4
,13
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[2] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA

[3] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA

[4] MIT, Dept Biol Engn, Cambridge, MA 02139 USA

[5] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[6] MIT, Dept Biol, Cambridge, MA 02139 USA

[7] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA

[8] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA

[9] MIT, Dept Chem Engn, Cambridge, MA 02139 USA

[10] Harvard Univ, Sch Med, Boston, MA 02115 USA

[11] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA

[12] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[13] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

来源：

CELL | 2014年 / 159卷 / 02期

基金：

美国国家卫生研究院; 瑞士国家科学基金会; 美国国家科学基金会;

关键词：

ZINC-FINGER NUCLEASES; GENE-EXPRESSION; HUMAN-CELLS; HOMOLOGOUS RECOMBINATION; CRE RECOMBINASE; LUNG-CANCER; VECTORS; SYSTEM; RNA; DNA;

D O I：

10.1016/j.cell.2014.09.014

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：

CRISPR-Cas9 is a versatile genome editing technology for studying the functions of genetic elements. To broadly enable the application of Cas9 in vivo, we established a Cre-dependent Cas9 knockin mouse. We demonstrated in vivo as well as ex vivo genome editing using adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells, and endothelial cells. Using these mice, we simultaneously modeled the dynamics of KRAS, p53, and LKB1, the top three significantly mutated genes in lung adenocarcinoma. Delivery of a single AAV vector in the lung generated loss-of-function mutations in p53 and Lkb1, as well as homology-directed repair-mediated Kras(G12D) mutations, leading to macroscopic tumors of adenocarcinoma pathology. Together, these results suggest that Cas9 mice empower a wide range of biological and disease modeling applications.

引用

页码：440 / 455

页数：16

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