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Genetically altered mouse models: the good, the bad, and the ugly
Tamizchelvi Thyagarajan1, Satish Totey, Mary Jo S Danton
1Functional Genomics Unit and Gene Targeting Facility, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30, Room 527, 30 Convent Drive, Bethesda, MD 20892, USA.
Summary
Gene targeting in mice creates valuable models for human disease research. While caution is needed for interpreting results, these genetically engineered animal models are crucial for understanding development and disease.
Area of Science:
- Genetics
- Developmental Biology
- Medical Research
Background:
- Targeted gene disruption in mice is a key method for creating models of human development and disease.
- Despite advances from the human genome project, the in vivo functions of many genes remain uncharacterized.
- Gene targeting has significantly advanced the understanding of gene functions, with many knockout models accurately reflecting human disease phenotypes.
Purpose of the Study:
- To evaluate the utility and limitations of gene targeting strategies in creating murine models for human development and disease.
- To address the controversy surrounding gene targeting due to unexpected or absent phenotypes in some models.
- To advocate for the cautious application of gene targeting, especially in complex fields like craniofacial and oral biology.
Main Methods:
- Utilizing gene targeting techniques to create knockout mouse models.
- Analyzing and interpreting in vivo phenotypes of genetically modified mice.
- Comparing murine model phenotypes with human disease manifestations.
Main Results:
- Gene targeting has proven impactful in delineating gene functions, with many models successfully mimicking human disease phenotypes.
- Some gene knockout models exhibit unexpected or no discernible phenotype, leading to debate about the strategy's overall value.
- Genes in craniofacial and oral biology often display pleiotropic roles, necessitating careful interpretation of knockout phenotypes.
Conclusions:
- Gene targeting is a valuable tool for studying gene function and disease, but requires cautious interpretation of results, particularly for genes with pleiotropic effects.
- The potential drawbacks of gene targeting are outweighed by its benefits in developing and testing therapeutic strategies before clinical application.
- Genetically engineered animal models are essential for future research into the molecular mechanisms of development, disease pathogenesis, diagnosis, prevention, and treatment.