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The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes
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The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes
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Journal Article
The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes
2025
Overview
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-Cre
Evdr
line which is widely used for brown fat research. Hemizygotes exhibit major brown and white fat transcriptomic dysregulation, indicating potential altered tissue function.
Ucp1-Cre
Evdr
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-Cre
Evdr
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-Cre
Evdr
transgene independently of intended genetic manipulations. Overall, comprehensive validation of transgenic mice is imperative to maximize discovery while mitigating unexpected, off-target effects.
UCP1 is involved in regulating thermogenesis, and the
Ucp1-Cre
mouse line has been widely used for studying brown fat. Here they show that this mouse line carries an extra copy of the
Ucp1
gene and displays unexpected changes in fat tissue function. Researchers should be cautious when interpreting studies using this model.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/63
/ 38/22
/ 49/39
/ 49/90
/ 49/91
/ 631/337
/ 64/60
/ 82/1
/ 82/29
/ 82/80
/ Adipose Tissue, Brown - metabolism
/ Adipose Tissue, White - metabolism
/ Animals
/ Bacterial artificial chromosomes
/ Body fat
/ Female
/ Humanities and Social Sciences
/ Male
/ Mice
/ Science
