CRISPR-Cas9 knockin mice for genome editing and cancer modeling.

Cell
Authors
Keywords
Abstract

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.

Year of Publication
2014
Journal
Cell
Volume
159
Issue
2
Pages
440-55
Date Published
2014 Oct 09
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2014.09.014
PubMed ID
25263330
PubMed Central ID
PMC4265475
Links
Grant list
HHSN268201000045C / HL / NHLBI NIH HHS / United States
R01 EB000244 / EB / NIBIB NIH HHS / United States
R01-CA133404 / CA / NCI NIH HHS / United States
U54 CA151884 / CA / NCI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
DP1-MH100706 / DP / NCCDPHP CDC HHS / United States
DK43351 / DK / NIDDK NIH HHS / United States
U54CA151884 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
R01 CA133404 / CA / NCI NIH HHS / United States
DP1 MH100706 / MH / NIMH NIH HHS / United States
P50 HG006193 / HG / NHGRI NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 DK097768 / DK / NIDDK NIH HHS / United States
R37 EB000244 / EB / NIBIB NIH HHS / United States
EB000244 / EB / NIBIB NIH HHS / United States
268201000045C / PHS HHS / United States
R01-NS 07312401 / NS / NINDS NIH HHS / United States