Tissue-specific and reversible RNA interference in transgenic mice.
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.
Dickins
Ross A
RA
Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA.
McJunkin
Katherine
K
Hernando
Eva
E
Premsrirut
Prem K
PK
Krizhanovsky
Valery
V
Burgess
Darren J
DJ
Kim
Sang Yong
SY
Cordon-Cardo
Carlos
C
Zender
Lars
L
Hannon
Gregory J
GJ
Lowe
Scott W
SW
D000818:Animals; D016503:Drug Delivery Systems; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics*; D011401:Promoter Regions, Genetic; D034622:RNA Interference / Q000502:physiology; D013752:Tetracycline
D013752:Tetracycline