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Published on: May 18, 2017
Cystic fibrosis in the mouse by targeted insertional mutagenesis
J R Dorin1, P Dickinson, E W Alton
1MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK.
Abstract:
Cystic fibrosis is a fatal genetic disorder which afflicts 50,000 people worldwide. A viable animal model would be invaluable for investigating and combating this disease. The mouse cystic fibrosis transmembrane conductance regulator gene was disrupted in embryonal stem cells using an insertional gene targeting vector. Germ-line chimaeras were derived and the offspring of heterozygous crosses studied. These homozygous mutant mice survive beyond weaning. In vivo electrophysiology demonstrates the predicted defect in chloride ion transport in these mice and can distinguish between each genotype. Histological analysis detects important hallmarks of human disease pathology, including abnormalities of the colon, lung and vas deferens. This insertional mouse mutation provides a valid model system for the development and testing of therapies for cystic fibrosis patients.
Insights
Scientists created a mouse model for cystic fibrosis by disrupting the cystic fibrosis transmembrane conductance regulator gene. These mice exhibit key disease characteristics, offering a valuable tool for developing new cystic fibrosis therapies.
Area of Science:
- Genetics
- Physiology
- Animal Models
Background:
- Cystic fibrosis is a fatal genetic disorder affecting 50,000 individuals globally.
- A validated animal model is crucial for understanding and treating cystic fibrosis.
- The cystic fibrosis transmembrane conductance regulator (CFTR) gene is implicated in the disease.
Purpose of the Study:
- To develop a mouse model for cystic fibrosis.
- To validate the model's utility in studying disease mechanisms and testing therapies.
Main Methods:
- Gene targeting was used to disrupt the mouse CFTR gene in embryonic stem cells.
- Germ-line chimeras were generated, and heterozygous crosses were studied.
- In vivo electrophysiology and histological analysis were performed on the offspring.
Main Results:
- Homozygous mutant mice, lacking functional CFTR, survived beyond weaning.
- Electrophysiology confirmed defective chloride ion transport, consistent with cystic fibrosis.
- Histological analysis revealed pathologies in the colon, lung, and vas deferens, mirroring human disease.
Conclusions:
- The developed insertional mouse mutation represents a valid animal model for cystic fibrosis.
- This model is suitable for investigating disease pathogenesis and evaluating potential therapeutic interventions.
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