Tissue-specific and reversible RNA interference in transgenic mice

Ross Alexander Dickins, Katherine McJunkin, Eva M Hernando-Monge, Prem K Premsrirut, Valery Krizhanovsky, Darren J Burgess, Sang Yong Kim, Carlos Cordon-Cardo, Lars Zender, Gregory J Hannon, Scott William Lowe

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138 Citations (Scopus)

Abstract

Genetically engineered mice provide powerful tools for understanding mammalian gene function. These models traditionally rely on gene overexpression from transgenes or targeted, irreversible gene mutation. By adapting the tetracycline (tet)-responsive system previously used for gene overexpression, we have developed a simple transgenic system to reversibly control endogenous gene expression using RNA interference (RNAi) in mice. Transgenic mice harboring a tet-responsive RNA polymerase II promoter driving a microRNA-based short hairpin RNA targeting the tumor suppressor Trp53 reversibly express short hairpin RNA when crossed with existing mouse strains expressing general or tissue-specific tet-on or tet-off transactivators. Reversible Trp53 knockdown can be achieved in several tissues, and restoring Trp53 expression in lymphomas whose development is promoted by Trp53 knockdown leads to tumor regression. By leaving the target gene unaltered, this approach permits tissue-specific, reversible regulation of endogenous gene expression in vivo, with potential broad application in basic biology and drug target validation.
Original languageEnglish
Pages (from-to)914 - 921
Number of pages8
JournalNature Genetics
Volume39
DOIs
Publication statusPublished - 2007
Externally publishedYes

Cite this

Dickins, R. A., McJunkin, K., Hernando-Monge, E. M., Premsrirut, P. K., Krizhanovsky, V., Burgess, D. J., Kim, S. Y., Cordon-Cardo, C., Zender, L., Hannon, G. J., & Lowe, S. W. (2007). Tissue-specific and reversible RNA interference in transgenic mice. Nature Genetics, 39, 914 - 921. https://doi.org/10.1038/ng2045