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<p>Bacterial artificial chromosome transgenic models, including most <i>Cre-recombinases</i>, 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 <i>Ucp1-Cre</i><sup><i>Evdr</i></sup> line which is widely used for brown fat research. Hemizygotes exhibit major brown and white fat transcriptomic dysregulation, indicating potential altered tissue function. <i>Ucp1-Cre</i><sup><i>Evdr</i></sup> 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, <i>Ucp1-Cre</i><sup><i>Evdr</i></sup> transgene retains an extra <i>Ucp1</i> 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 <i>Ucp1-Cre</i><sup><i>Evdr</i></sup> transgene independently of intended genetic manipulations. Overall, comprehensive validation of transgenic mice is imperative to maximize discovery while mitigating unexpected, off-target effects.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月17日

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  • 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 Sanchez-Gurmaches

摘要

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.