The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes
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-Cre E...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54763-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594591559188480 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Manasi Suchit Halurkar |
| collection | DOAJ |
| description | 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-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. |
| format | Article |
| id | doaj-art-f3ddb238cc3344feadcfe3711a22da8d |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f3ddb238cc3344feadcfe3711a22da8d2025-01-19T12:31:05ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-024-54763-4The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypesManasi Suchit Halurkar0Oto Inoue1Archana Singh2Rajib Mukherjee3Meghana Ginugu4Christopher Ahn5Christian Louis Bonatto Paese6Molly Duszynski7Samantha A. Brugmann8Hee-Woong Lim9Joan Sanchez-Gurmaches10Division of Endocrinology, Cincinnati Children’s Hospital Medical CenterDivision of Endocrinology, Cincinnati Children’s Hospital Medical CenterDivision of Endocrinology, Cincinnati Children’s Hospital Medical CenterDivision of Endocrinology, Cincinnati Children’s Hospital Medical CenterDivision of Endocrinology, Cincinnati Children’s Hospital Medical CenterDivision of Biomedical Informatics, Cincinnati Children’s Hospital Medical CenterDivision of Developmental Biology, Cincinnati Children’s Hospital Medical CenterDivision of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical CenterDivision of Developmental Biology, Cincinnati Children’s Hospital Medical CenterDivision of Biomedical Informatics, Cincinnati Children’s Hospital Medical CenterDivision of Endocrinology, Cincinnati Children’s Hospital Medical CenterAbstract 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.https://doi.org/10.1038/s41467-024-54763-4 |
| spellingShingle | 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 The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes Nature Communications |
| title | The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes |
| title_full | The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes |
| title_fullStr | The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes |
| title_full_unstemmed | The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes |
| title_short | The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes |
| title_sort | widely used ucp1 cre transgene elicits complex developmental and metabolic phenotypes |
| url | https://doi.org/10.1038/s41467-024-54763-4 |
| work_keys_str_mv | AT manasisuchithalurkar thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT otoinoue thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT archanasingh thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT rajibmukherjee thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT meghanaginugu thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT christopherahn thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT christianlouisbonattopaese thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT mollyduszynski thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT samanthaabrugmann thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT heewoonglim thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT joansanchezgurmaches thewidelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT manasisuchithalurkar widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT otoinoue widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT archanasingh widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT rajibmukherjee widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT meghanaginugu widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT christopherahn widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT christianlouisbonattopaese widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT mollyduszynski widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT samanthaabrugmann widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT heewoonglim widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes AT joansanchezgurmaches widelyuseducp1cretransgeneelicitscomplexdevelopmentalandmetabolicphenotypes |