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

Motoi Yamashita, Chihiro Ogawa, Baihao Zhang, Tetsuro Kobayashi, Aneela Nomura, Clive Barker, Chengcheng Zou, Satoshi Yamanaka, Ken-ichiro Hayashi, Yoichi Shinkai, Kazuyo Moro, Sidonia Fargarasan, Koshi Imami, Jun Seita, Fumiyuki Shirai, Tatsuya Sawasaki, Masato T. Kanemaki and Ichiro Taniuchi ()
Additional contact information
Motoi Yamashita: RIKEN Center for Integrative Medical Sciences (IMS)
Chihiro Ogawa: RIKEN Center for Integrative Medical Sciences (IMS)
Baihao Zhang: RIKEN Center for Integrative Medical Sciences (IMS)
Tetsuro Kobayashi: RIKEN Center for Integrative Medical Sciences (IMS)
Aneela Nomura: RIKEN Center for Integrative Medical Sciences (IMS)
Clive Barker: RIKEN Center for Integrative Medical Sciences (IMS)
Chengcheng Zou: RIKEN Center for Integrative Medical Sciences (IMS)
Satoshi Yamanaka: Ehime University
Ken-ichiro Hayashi: Okayama University of Science
Yoichi Shinkai: RIKEN Cluster for Pioneering Research
Kazuyo Moro: RIKEN Center for Integrative Medical Sciences (IMS)
Sidonia Fargarasan: RIKEN Center for Integrative Medical Sciences (IMS)
Koshi Imami: RIKEN Center for Integrative Medical Sciences (IMS)
Jun Seita: RIKEN Center for Integrative Medical Sciences (IMS)
Fumiyuki Shirai: RIKEN Center for Sustainable Resource Science
Tatsuya Sawasaki: Ehime University
Masato T. Kanemaki: National Institute of Genetics
Ichiro Taniuchi: RIKEN Center for Integrative Medical Sciences (IMS)

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54308-9

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