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

doi:10.1016/j.cell.2014.09.014

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 journal › Article › peer-review

1406 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 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.

Original language	English
Pages (from-to)	440-455
Number of pages	16
Journal	Cell
Volume	159
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2014.09.014
State	Published - 9 Oct 2014
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Inc.

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Platt, R. J., Chen, S., Zhou, Y., Yim, M. J., Swiech, L., Kempton, H. R., Dahlman, J. E., Parnas, O., Eisenhaure, T. M., Jovanovic, M., Graham, D. B., Jhunjhunwala, S., Heidenreich, M., Xavier, R. J., Langer, R., Anderson, D. G., Hacohen, N., Regev, A., Feng, G., ... Zhang, F. (2014). CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell, 159(2), 440-455. https://doi.org/10.1016/j.cell.2014.09.014

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title = "CRISPR-Cas9 knockin mice for genome editing and cancer modeling",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",

year = "2014",

month = oct,

day = "9",

doi = "10.1016/j.cell.2014.09.014",

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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 2014, 'CRISPR-Cas9 knockin mice for genome editing and cancer modeling', Cell, vol. 159, no. 2, pp. 440-455. https://doi.org/10.1016/j.cell.2014.09.014

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AU - Platt, Randall J.

AU - Chen, Sidi

AU - Zhou, Yang

AU - Yim, Michael J.

AU - Swiech, Lukasz

AU - Kempton, Hannah R.

AU - Dahlman, James E.

AU - Parnas, Oren

AU - Eisenhaure, Thomas M.

AU - Jovanovic, Marko

AU - Graham, Daniel B.

AU - Jhunjhunwala, Siddharth

AU - Heidenreich, Matthias

AU - Xavier, Ramnik J.

AU - Langer, Robert

AU - Anderson, Daniel G.

AU - Hacohen, Nir

AU - Regev, Aviv

AU - Feng, Guoping

AU - Sharp, Phillip A.

AU - Zhang, Feng

PY - 2014/10/9

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AB - 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.

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CRISPR-Cas9 knockin mice for genome editing and cancer modeling

Abstract

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