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Cardiac-Specific Cre Induces Age-Dependent Dilated Cardiomyopathy (DCM) in Mice
Taha Rehmani1, Maysoon Salih2, Balwant S Tuana3
1Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. trehmani@uottawa.ca.
Abstract:
The genetic modification of the mouse genome using the cre-lox system has been an invaluable tool in deciphering gene and protein function in a temporal and/or spatial manner. However, it has its pitfalls, as researchers have shown that the unregulated expression of cre recombinase can cause DNA damage, the consequences of which can be very detrimental to mouse health. Previously published literature on the most utilized cardiac-specific cre, αMHC-cre, mouse model exhibited a nonlethal hypertrophic cardiomyopathy (HCM) with aging. However, using the same αMHC-cre mice, we observed a cardiac pathology, resulting in complete lethality by 11 months of age. Echocardiography and histology revealed that the αMHC-cre mice were displaying symptoms of dilated cardiomyopathy (DCM) by seven months of age, which ultimately led to their demise in the absence of any HCM at any age. Molecular analysis showed that this phenotype was associated with the DNA damage response through the downregulation of activated p38 and increased expression of JNK, p53, and Bax, known inducers of myocyte death resulting in fibrosis. Our data urges strong caution when interpreting the phenotypic impact of gene responses using αMHC-cre mice, since a lethal DCM was induced by the cre driver in an age-dependent manner in this commonly utilized model system.
Insights
The widely used alphaMHC-cre mouse model can induce lethal dilated cardiomyopathy (DCM) in aging mice due to unregulated cre recombinase expression, not hypertrophic cardiomyopathy (HCM). This highlights critical safety concerns for genetic research using this model.
Area of Science:
- Genetics
- Cardiovascular Biology
- Molecular Biology
Background:
- The Cre-lox system enables temporal and spatial gene manipulation in mice.
- Unregulated Cre recombinase expression can lead to detrimental DNA damage and health consequences.
- Previous studies reported nonlethal hypertrophic cardiomyopathy (HCM) in aging alphaMHC-cre mice.
Purpose of the Study:
- To investigate the cardiac pathology and lethality observed in alphaMHC-cre mice.
- To determine the underlying molecular mechanisms of the observed cardiac phenotype.
- To caution researchers on the interpretation of gene function studies using the alphaMHC-cre model.
Main Methods:
- Utilized alphaMHC-cre mouse model.
- Performed echocardiography and histology for cardiac assessment.
- Conducted molecular analysis to examine DNA damage response pathways.
Main Results:
- Observed complete lethality in alphaMHC-cre mice by 11 months of age.
- Echocardiography and histology revealed dilated cardiomyopathy (DCM) by seven months.
- Molecular analysis indicated a DNA damage response with altered p38, JNK, p53, and Bax expression, leading to myocyte death and fibrosis.
Conclusions:
- The alphaMHC-cre driver itself can induce a lethal, age-dependent DCM.
- The observed phenotype is linked to DNA damage response pathways and myocyte apoptosis.
- Researchers must exercise caution when interpreting results from studies using the alphaMHC-cre mouse model due to potential Cre-induced toxicity.
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