CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling
Author(s)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; Heidenreich, Matthias; Xavier, Ramnik J.; Langer, Robert; Hacohen, Nir; Regev, Aviv; Feng, Guoping; Sharp, Phillip A.; Zhang, Feng; Platt, Randall; Anderson, Daniel Griffith; Yim, Michael J.; Kempton, Hannah R.; Dahlman, James E.; Sharp, Phillip A.; ... Show more Show less
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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[superscript 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.
DepartmentInstitute for Medical Engineering and Science; David H. Koch Institute for Integrative Cancer Research at MIT; Harvard University--MIT Division of Health Sciences and Technology; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Massachusetts Institute of Technology. Department of Chemical Engineering; McGovern Institute for Brain Research at MIT
Platt, Randall J., Sidi Chen, Yang Zhou, Michael J. Yim, Lukasz Swiech, Hannah R. Kempton, James E. Dahlman, et al. “CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling.” Cell 159, no. 2 (October 2014): 440–455.
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