Tissue-specific and reversible RNA interference in transgenic mice

Dickins, R. A., McJunkin, K., Hernando, E., Premsrirut, P. K., Krizhanovsky, V., Burgess, D. J., Kim, S. Y., Cordon-Cardo, C., Zender, L., Hannon, G. J., Lowe, S. W. (July 2007) Tissue-specific and reversible RNA interference in transgenic mice. Nat Genet, 39 (7). 914 - 921. ISSN 1061-4036 (Print)

URL: http://www.ncbi.nlm.nih.gov/pubmed/17572676
DOI: 10.1038/ng2045

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.

Item Type: Paper
Uncontrolled Keywords: GENE-EXPRESSION MAMMALIAN-CELLS P53 RESTORATION IN-VIVO MOUSE PHENOTYPES APOPTOSIS MYC LYMPHOMAGENESIS TUMORIGENESIS
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNAi
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA expression > promoter > TET responsive promoter
diseases & disorders > cancer > cancer types > lymphoma
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA

organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > transgenic animal
CSHL Authors:
Communities: CSHL labs > Hannon lab
CSHL labs > Lowe lab
Watson School > Publications
Depositing User: CSHL Librarian
Date: July 2007
Date Deposited: 30 Nov 2011 20:50
Last Modified: 22 Sep 2014 14:54
Related URLs:
URI: http://repository.cshl.edu/id/eprint/23001

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