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An inactivating caspase 11 passenger mutation originating from the 129 murine strain in mice targeted for c-IAP1
Niall S Kenneth1, J Michael Younger, Elizabeth D Hughes
1Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Abstract:
A recent study revealed that ES (embryonic stem) cell lines derived from the 129 murine strain carry an inactivating mutation within the caspase 11 gene (Casp4) locus [Kayagaki, Warming, Lamkanfi, Vande Walle, Louie, Dong, Newton, Qu, Liu, Heldens, Zhang, Lee, Roose-Girma and Dixit (2011) Nature 479, 117-121]. Thus, if 129 ES cells are used to target genes closely linked to caspase 11, the resulting mice might also carry the caspase 11 deficiency as a passenger mutation. In the present study, we examined the genetic loci of mice targeted for the closely linked c-IAP (cellular inhibitor of apoptosis) genes, which were generated in 129 ES cells, and found that, despite extensive backcrossing into a C57BL/6 background, c-IAP1(-/-) animals are also deficient in caspase 11. Consequently, data obtained from these mice should be re-evaluated in this new context.
Insights
Embryonic stem cells from the 129 strain have a caspase 11 gene mutation. This mutation can affect research on related genes, impacting findings in mice even after backcrossing.
Area of Science:
- Immunology
- Genetics
- Cell Biology
Background:
- Embryonic stem (ES) cells from the 129 murine strain possess an inactivating mutation in the caspase 11 gene (Casp4).
- Using these 129 ES cells for gene targeting near the caspase 11 locus may introduce a passenger mutation, leading to caspase 11 deficiency in the resulting mice.
- This potential confounding factor necessitates careful consideration when interpreting experimental data from such models.
Purpose of the Study:
- To investigate the genetic integrity of mice targeted for cellular inhibitor of apoptosis (c-IAP) genes, specifically c-IAP1.
- To determine if the caspase 11 deficiency, originating from the 129 ES cell background, persists in c-IAP1 knockout mice.
- To highlight the need for re-evaluation of data from these genetically modified mouse models.
Main Methods:
- Generation of gene-targeted mice using 129 ES cells for c-IAP genes.
- Extensive backcrossing of targeted mice into the C57BL/6 genetic background.
- Genotyping and functional assays to assess caspase 11 status in c-IAP1 knockout animals.
Main Results:
- Mice with targeted deletion of c-IAP1 (c-IAP1(-/-)), generated using 129 ES cells, were found to be deficient in caspase 11.
- This caspase 11 deficiency was observed despite extensive backcrossing into the C57BL/6 background, indicating the mutation's persistence.
- The study confirms that the passenger mutation in caspase 11 is linked to the use of 129 ES cells.
Conclusions:
- The genetic background of ES cells used for gene targeting is critical and can introduce unintended mutations.
- Researchers using c-IAP1(-/-) mice derived from 129 ES cells must account for the concurrent caspase 11 deficiency.
- Experimental data derived from these mice require re-evaluation in light of the confirmed caspase 11 deficiency.
