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

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 and Joan Sanchez-Gurmaches ()
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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
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
Molly Duszynski: Cincinnati Children’s Hospital Medical Center
Samantha A. Brugmann: Cincinnati Children’s Hospital Medical Center
Hee-Woong Lim: Cincinnati Children’s Hospital Medical Center
Joan Sanchez-Gurmaches: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-54763-4

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