Development of a novel conditional knockdown mouse based on YB-1 protein degradation.

Abstract

To clarify the pathogenic mechanism of disease and establish effective therapies, animal disease models that can be dynamically analyzed are urgently required. Knockout mouse models and conditional genetically engineered mouse models were developed to analyze genes and proteins involved in disease. However, these methods have drawbacks, including embryonic lethality, side effects and low efficiency. To address this issue, we created a novel transgenic mouse model in which the YB1 gene was fused with a destabilizing domain (DD), named the YB1-DD mouse. YB-1 is widely expressed throughout development and has been implicated as a cell survival factor. Newly synthesized DD proteins are degraded through the proteasome pathway, but their degradation can be blocked with trimethoprim (TMP). In this study, we established a novel conditional knockdown mouse model that enables targeting of protein degradation directly; this model resulted in dose-dependent regulation of the target protein YB-1 by the ligand TMP in YB1 heterozygous mice. Since this conditional knockdown mouse model appears to be functional, it has potential as a useful disease model based on direct protein degradation control.