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Creation and preliminary characterization of a Tp53 knockout rat
Aaron McCoy1, Cynthia L Besch-Williford, Craig L Franklin
1Sigma Advanced Genetic Engineering Labs, Sigma-Aldrich Corporation, St Louis, MO 63146, USA.
Abstract:
The tumor suppressor TP53 plays a crucial role in cancer biology, and the TP53 gene is the most mutated gene in human cancer. Trp53 knockout mouse models have been widely used in cancer etiology studies and in search for a cure of cancer with some limitations that other model organisms might help overcome. Via pronuclear microinjection of zinc finger nucleases (ZFNs), we created a Tp53 knockout rat that contains an 11-bp deletion in exon 3, resulting in a frameshift and premature terminations in the open reading frame. In cohorts of 25 homozygous (Tp53(Δ11/Δ11)), 37 heterozygous (Tp53(Δ11/+)) and 30 wild-type rats, the Tp53(Δ11/Δ11) rats lived an average of 126 days before death or removal from study because of clinical signs of abnormality or formation of tumors. Half of Tp53(Δ11/+) were removed from study by 1 year of age because of tumor formation. Both Tp53(Δ11/+) and Tp53(Δ11/Δ11) rats developed a wide spectrum of tumors, most commonly sarcomas. Interestingly, there was a strikingly high incidence of brain lesions, especially in Tp53(Δ11/Δ11) animals. We believe that this mutant rat line will be useful in studying cancer types rarely observed in mice and in carcinogenicity assays for drug development.
Insights
A new Tp53 knockout rat model was developed to study cancer. These rats develop a wide spectrum of tumors, including sarcomas and brain lesions, offering new research avenues.
Area of Science:
- Oncology
- Genetics
- Animal Models
Background:
- The TP53 gene is frequently mutated in human cancers.
- Trp53 knockout mouse models are used in cancer research but have limitations.
- Alternative model organisms may overcome limitations in current cancer models.
Purpose of the Study:
- To create and characterize a Tp53 knockout rat model for cancer research.
- To evaluate the utility of this rat model in studying cancer etiology and drug development.
Main Methods:
- Zinc finger nucleases (ZFNs) were used for pronuclear microinjection to create the knockout.
- An 11-bp deletion in exon 3 of the Tp53 gene resulted in a frameshift mutation.
- Homozygous (Tp53(Δ11/Δ11)), heterozygous (Tp53(Δ11/+)), and wild-type rat cohorts were studied.
Main Results:
- Tp53(Δ11/Δ11) rats had an average lifespan of 126 days due to tumors or clinical abnormalities.
- Half of Tp53(Δ11/+) rats developed tumors by 1 year of age.
- Both knockout genotypes developed diverse tumors, primarily sarcomas, with a high incidence of brain lesions in homozygous rats.
Conclusions:
- The Tp53 knockout rat is a valuable model for studying various cancer types, including those rare in mice.
- This model can be utilized for carcinogenicity assays in drug development.
- The high incidence of brain lesions warrants further investigation.
