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Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1999 US/Japan Conference (2000)

Chapter: Defining Phenotype in Genetically Engineered Mice

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Suggested Citation:"Defining Phenotype in Genetically Engineered Mice." National Research Council. 2000. Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1999 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9987.
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Defining Phenotype in Genetically Engineered Mice

Norikazu Tamaoki

Tokai University School of Medicine

Kanagawa, Japan

INTRODUCTION

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.

HISTORICAL DEVELOPMENT

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).

Suggested Citation:"Defining Phenotype in Genetically Engineered Mice." National Research Council. 2000. Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1999 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9987.
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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

CONCLUSIONS

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.

REFERENCES

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.

Suggested Citation:"Defining Phenotype in Genetically Engineered Mice." National Research Council. 2000. Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1999 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9987.
×
Page 130
Suggested Citation:"Defining Phenotype in Genetically Engineered Mice." National Research Council. 2000. Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1999 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9987.
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US/Japan meetings on laboratory animal science have been held virtually every year since 1980 under the US/Japan Cooperative Program on Science and Technology. Over the years these meetings have resulted in a number of important documents including the Manual of Microbiologic Monitoring of Laboratory Animals published in 1994 and the article Establishment and Preservation of Reference Inbred Strains of Rats for General Purposes. In addition to these publications, the meetings have been instrumental in increasing awareness of the need for microbiologic monitoring of laboratory rodents and the need for genetic definition and monitoring of mice and rats.

In cooperation with the Comparative Medicine section of NCRR/NIH, the ILAR Council and staff are pleased to become the host for this important annual meeting and look forward to participating in future meetings. The support and sponsorship of NCRR (P40 RR 11611) in the United States and the Central Institute for Experimental Animals in Japan are gratefully acknowledged. Bringing together the leading scientists in the field of laboratory animal care has resulted in increased understanding of American and Japanese approaches to laboratory animal science and should continue to strengthen efforts to harmonize approaches aimed at resolving common challenges in the use of animal models for biomedical research and testing. This effort to improve understanding and cooperation between Japan and the United States should also be useful in developing similar interaction with other regions of the world including Europe, Australia, and Southeast Asia.

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