Inducible transgenic rat model for diabetes mellitus based on shRNA-mediated gene knockdown.
The rat is an important animal model in biomedical research, but gene targeting technology is not established for this species. Therefore, we aimed to produce transgenic knockdown rats using shRNA technology and pronuclear microinjection. To this purpose, we employed a tetracycline-inducible shRNA expression system targeting the insulin receptor (IR). Doxycycline (DOX) treatment of the resulting transgenic rats led to a dose-dependent and reversible increase in blood glucose caused by ubiquitous inhibition of IR expression and signalling. We could neither detect an interferon response nor disturbances in microRNA processing after DOX treatment excluding toxic effects of shRNA expression. Low dose DOX treatment induced a chronic state of diabetes mellitus. In conclusion, we have developed a technology which allows the specific, inducible, and reversible suppression of any gene of interest in the rat. Our first transgenic rat line generated with this method represents an inducible model for diabetes mellitus.
Kotnik
Katarina
K
Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.
Popova
Elena
E
Todiras
Mihail
M
Mori
Marcelo A
MA
Alenina
Natalia
N
Seibler
Jost
J
Bader
Michael
M