Generating viable mice with heritable embryonically lethal mutations using the CRISPR-Cas9 system in two-cell embryos

Yi Wu, Jing Zhang, Boya Peng, Dan Tian, Dong Zhang, Yang Li, Xiaoyu Feng, Jinghao Liu, Jun Li, Teng Zhang, Xiaoyong Liu, Jing Lu, Baian Chen () and Songlin Wang ()
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Yi Wu: Capital Medical University
Jing Zhang: Capital Medical University
Boya Peng: Capital Medical University
Dan Tian: Capital Medical University
Dong Zhang: Capital Medical University
Yang Li: Capital Medical University
Xiaoyu Feng: Capital Medical University
Jinghao Liu: Peking University
Jun Li: Peking University
Teng Zhang: Capital Medical University
Xiaoyong Liu: Capital Medical University
Jing Lu: Capital Medical University
Baian Chen: Capital Medical University
Songlin Wang: Capital Medical University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract A substantial number of mouse genes, about 25%, are embryonically lethal when knocked out. Using current genetic tools, such as the CRISPR-Cas9 system, it is difficult—or even impossible—to produce viable mice with heritable embryonically lethal mutations. Here, we establish a one-step method for microinjection of CRISPR reagents into one blastomere of two-cell embryos to generate viable chimeric founder mice with a heritable embryonically lethal mutation, of either Virma or Dpm1. By examining founder mice, we identify a phenotype and role of Virma in regulating kidney metabolism in adult mice. Additionally, we generate knockout mice with a heritable postnatally lethal mutation, of either Slc17a5 or Ctla-4, and study its function in vivo. This one-step method provides a convenient system that rapidly generates knockout mice possessing lethal phenotypes. This allows relatively easy in vivo study of the associated genes’ functions.

Date: 2019
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DOI: 10.1038/s41467-019-10748-2

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