CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling

Platt, Randall J.; Chen, Sidi; Zhou, Yang; Yim, Michael J.; Swiech, Lukasz; Kempton, Hannah R.; Dahlman, James E.; Parnas, Oren; Eisenhaure, Thomas M.; Jovanovic, Marko; Graham, Daniel B.; Jhunjhunwala, Siddharth; Xavier, Ramnik J.; Langer, Robert; Anderson, Daniel G.; Hacohen, Nir; Regev, Aviv; Feng, Guoping; Sharp, Phillip A.; Zhang, Feng

doi:10.1016/j.cell.2014.09.014

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CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling

Published Date:

Sep 25 2014

Publisher's site:

http://dx.doi.org/10.1016/j.cell.2014.09.014 New Site Icon

Source:

Cell. 2014; 159(2):440-455.

[PDF-3.28 MB]

Details:

Personal Authors:

Platt, Randall J. ; Chen, Sidi ; Zhou, Yang ; Yim, Michael J. ; Swiech, Lukasz ; ... More ▼

Keywords:

[+]

Pubmed ID:

25263330

Pubmed Central ID:

PMC4265475

Description:

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.

Document Type:

Journal Article

Collection(s):

CDC Public Access

Funding:

268201000045C/PHS HHS/United States
DK43351/DK/NIDDK NIH HHS/United States
DP1 MH100706/MH/NIMH NIH HHS/United States
DP1-MH100706/DP/NCCDPHP CDC HHS/United States
EB000244/EB/NIBIB NIH HHS/United States
P30 CA014051/CA/NCI NIH HHS/United States
P30 DK043351/DK/NIDDK NIH HHS/United States
P30-CA14051/CA/NCI NIH HHS/United States
P50 HG006193/HG/NHGRI NIH HHS/United States
P50 HG006193/HG/NHGRI NIH HHS/United States
R01 DK097768/DK/NIDDK NIH HHS/United States
R01-CA133404/CA/NCI NIH HHS/United States
R01-NS 07312401/NS/NINDS NIH HHS/United States
U54 CA151884/CA/NCI NIH HHS/United States
U54CA151884/CA/NCI NIH HHS/United States
Howard Hughes Medical Institute/United States

Supporting Files:

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