Dow, L.E. et al. Nat. Biotechnol. doi:10.1038/nbt.3155 (18 February 2015).

Many genetically engineered mouse models have been generated with the CRISPR (clustered, regularly interspaced, short palindromic repeats)-Cas9 system, but embryonic lethality caused by some mutations has prevented the study of their function in adult animals. Dow et al. circumvented this bottleneck by expressing a doxycycline-inducible Cas9 nuclease or nickase together with specific guide RNAs in mouse embryonic stem cells (ESCs). Induction of Cas9 expression led to biallelic modifications in almost 50% of the targeted tumor suppressor genes. Mice generated from these ESCs showed hyperplastic lesions in their intestines, recapitulating a phenotype seen with the disruption of tumor suppressor genes in adult animals. This inducible CRISPR system can be multiplexed to up to six guide RNAs and will enable rapid in vivo loss-of-function studies.