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

Platt RJ, Chen S, Zhou Y, Yim MJ, Swiech L, Kempton HR, Dahlman JE, Parnas O, Eisenhaure TM, Jovanovic M, Graham DB, Jhunjhunwala S, Heidenreich M, Xavier RJ, Langer R, Anderson DG, Hacohen N, Regev A, Feng G, Sharp PA, Zhang F
Cell. 2014 159 (2): 440-55

PMID: 25263330 · PMCID: PMC4265475 · DOI:10.1016/j.cell.2014.09.014

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

MeSH Terms (14)

Adenocarcinoma Animals Clustered Regularly Interspaced Short Palindromic Repeats Dendritic Cells Disease Models, Animal Gene Knock-In Techniques Genes, Tumor Suppressor Genetic Engineering Genetic Vectors Lentivirus Lung Neoplasms Mice Mice, Transgenic Oncogenes

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