CRISPR-Cas9 knockin mice for genome editing and cancer modeling

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1351 Scopus citations

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 KrasG12D 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.

Original languageAmerican English
Pages (from-to)440-455
Number of pages16
JournalCell
Volume159
Issue number2
DOIs
StatePublished - 9 Oct 2014
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Inc.

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