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The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes

Author

Listed:
  • Manasi Suchit Halurkar

    (Cincinnati Children’s Hospital Medical Center)

  • Oto Inoue

    (Cincinnati Children’s Hospital Medical Center)

  • Archana Singh

    (Cincinnati Children’s Hospital Medical Center)

  • Rajib Mukherjee

    (Cincinnati Children’s Hospital Medical Center
    Suite 302)

  • Meghana Ginugu

    (Cincinnati Children’s Hospital Medical Center)

  • Christopher Ahn

    (Cincinnati Children’s Hospital Medical Center)

  • Christian Louis Bonatto Paese

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Molly Duszynski

    (Cincinnati Children’s Hospital Medical Center)

  • Samantha A. Brugmann

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine
    University of Cincinnati College of Medicine)

  • Hee-Woong Lim

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Joan Sanchez-Gurmaches

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center)

Abstract

Bacterial artificial chromosome transgenic models, including most Cre-recombinases, enable potent interrogation of gene function in vivo but require rigorous validation as limitations emerge. Due to its high relevance to metabolic studies, we perform comprehensive analysis of the Ucp1-CreEvdr line which is widely used for brown fat research. Hemizygotes exhibit major brown and white fat transcriptomic dysregulation, indicating potential altered tissue function. Ucp1-CreEvdr homozygotes also show high mortality, tissue specific growth defects, and craniofacial abnormalities. Mapping the transgene insertion site reveals insertion in chromosome 1 accompanied by large genomic alterations disrupting several genes expressed in a range of tissues. Notably, Ucp1-CreEvdr transgene retains an extra Ucp1 gene copy that may be highly expressed under high thermogenic burden. Our multi-faceted analysis highlights a complex phenotype arising from the presence of the Ucp1-CreEvdr transgene independently of intended genetic manipulations. Overall, comprehensive validation of transgenic mice is imperative to maximize discovery while mitigating unexpected, off-target effects.

Suggested Citation

  • Manasi Suchit Halurkar & Oto Inoue & Archana Singh & Rajib Mukherjee & Meghana Ginugu & Christopher Ahn & Christian Louis Bonatto Paese & Molly Duszynski & Samantha A. Brugmann & Hee-Woong Lim & Joan , 2025. "The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-54763-4
    DOI: 10.1038/s41467-024-54763-4
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    References listed on IDEAS

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