Defining Phenotype in Genetically Engineered Mice
Tokai University School of Medicine
Genetically engineered mice have become popular tools in recent biomedical research. However, only a few among thousands of genetically engineered mice so far reported have been established as laboratory animals that have controlled quality and are being produced and used on a large scale. The aims of defining phenotype in genetically engineered mice are as follows: (1) to define clearly the difference between genetically engineered animals produced for the purpose of elucidating the function of a gene or genes in vivo and laboratory animals used as a tool for studying the mechanism of diseases or testing drugs in vivo; and (2) to define clearly the difference among “genotype, ” “phenotype,” and “dramatype.” Dramatype, which is an altered function of the organism induced by changes in the environment and phenomena seen in the disease state, is the most important characteristic of laboratory animals.
The following two examples of genetically engineered mice have been developed as useful laboratory animals in the biomedical field: the TgPVR21 mouse (poliovirus receptor transgenic mouse) and the ras H2 mouse (human proto-ras transgenic mouse).
TgPVR21 Mouse (Poliovirus Receptor Transgenic Mouse)
1990-1991: Establishment of human poliovirus receptor transgenic mice
1991-1993: Establishment as a laboratory animal (standardization of characters and successful large-scale production) and development of methods for neurovirulence testing and safety assurance by castration (Levenbook and Nomura 1997)
1993-1995: World Health Organization (WHO) collaborative study of TgPVR21, 1st phase
1995-1997: WHO collaborative study of TgPVR21, 2nd phase
1997-1999: WHO collaborative study of TgPVR21, 3rd phase
1999: Approval of neurovirulence test of oral poliovirus vaccine alternative for monkeys by WHO Expert Committee on Biological Standardization
ras H2 Mouse (Human Proto-ras Transgenic Mouse)
1988: Establishment of human proto-ras gene transgenic mouse
1990-1992: Backcrossing and establishment of congenics
1992-1996: Validation study for carcinogenicity testing in Japan (Yamamoto and others 1998)
1996-1999: Validation study for rapid carcinogenicity testing in the United States, the European Union, and Japan
As shown above, establishment of a novel laboratory animal from a genetically engineered animal is a lengthy process and requires many steps as follows: (1) establishing of a genetically engineered animal; (2) phenotyping and selection of candidate animals; (3) study of functions in purpose-oriented environments or experimentation (dramatyping); and (4) establishment of a human disease model as a laboratory animal.
Levenbook, I., and T. Nomura. 1997. Development of a neurovirulent testing system for oral poliovirus vaccine with transgenic mice. Lab. Anim. Sci. 47:118-120.
Yamamoto, S., K. Urano, H. Koizumi, S. Wakana, K. Hioki, K. Mitsumori, Y. Kurokawa, Y. Hayashi, and T. Nomura. 1998. Validation of transgenic mice carrying the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing. Environ. Health Perspect. 106(Suppl 1):57-69.