Journal
CELL
Volume 159, Issue 2, Pages 440-455Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.09.014
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Funding
- Swanson Biotechnology Center
- National Science Foundation Graduate Research Fellowship [1122374]
- Simons Center for the Social Brain at MIT
- NDSEG
- NSF
- MIT
- Swiss National Science Foundation (SNF)
- Marie Sklodowska-Curie IOF
- Helmsley CharitableTrust
- Human Frontiers Science Program
- NHGRI CEGS [P50 HG006193]
- HHMI
- Klarman Cell Observatory
- NIH Centers of Cancer Nanotechnology Excellence grant [U54CA151884]
- NIH Controlled Release grant [EB000244]
- National Heart, Lung, and Blood Institute, National Institutes of Health [HHSN268201000045C]
- McGovern Internal Funding Poitras Gift [1631119]
- Stanley Center
- SFARI/Simons Foundation [6927482]
- Nancy Lurie Marks Family Foundation [6928117]
- United States Public Health Service from the National Institutes of Health [R01-CA133404]
- MIT-Harvard Center for Cancer Nanotechnology Excellence Grant from the National Cancer Institute [U54 CA151884]
- Marie D. and Pierre Casimir-Lambert Fund
- SkTech/MIT Initiative Grant from the Skolkovo Foundation
- Koch Institute Support (core) grant from the National Cancer Institute [P30-CA14051]
- NIMH through NIH [DP1-MH100706]
- NINDS through NIH [R01-NS 07312401]
- NSF Waterman Award
- Keck Foundation
- Damon Runyon Foundation
- Searle Scholars Foundation
- Klingenstein Foundation
- Vallee Foundation
- Merkin Foundation
- Simons Foundation
- Bob Metcalfe
- [DK43351]
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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.
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