Cell-type specific, inducible and acute degradation of targeted protein in mice by two degron systems

Yamashita M, Ogawa C, Zhang B, Kobayashi T, Nomura A, Barker C, Zou C, Yamanaka S, Hayashi KI, Shinkai Y, Moro K, Fargarasan S, Imami K, Seita J, Shirai F, Sawasaki T, Kanemaki MT, Taniuchi I.

Despite its broad application in in vitro studies, the application of targeted protein degradation (TPD) to animal models faces considerable challenges. Here, we develop inducible and cell-type specific TPD systems in mice using two degron systems: Oryza sativa TIR1F74G (OsTIR1)-auxin-inducible degron 2 (AID2) and human cereblon (hCRBN)-SALL4 degron (S4D). Efficient degradation of Satb1Venus protein by these systems recapitulates phenotypes observed in the Satb1-deficient mice. These TPD are successfully applied in both the fetal and neonatal stages. The OsTIR1-AID2 system proves to be effective for membrane proteins such as PD-1, emulating the effects of the anti-PD-1 antibody. Degradation of Bcl11b reveals a role of Bcl11b which was not characterized by the Cre-loxP system. Collectively, in vivo TPD technologies developed in this study enable inducible, temporal, and cell type-specific depletion of target proteins with high efficacy in mice. These technologies have a wide range of applications in the diverse fields of biological and medical research.
© 2024. The Author(s).

Nat Commun
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doi: 10.1038/s41467-024-54308-9