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An ENU-induced mutant archive for gene targeting in rats

Nature Genetics volume 40, pages 514–515 (2008)Cite this article

To the editor:

Although the laboratory rat is increasingly being used as a mammalian model in biomedical research, no technology exists thus far for the production of in vivo genetically engineered mutations equivalent to knockout or knock-in mice because of the lack of development of functional embryonic stem cells in this species. Rat spermatogonial stem cells may possibly have greater potential use for genetic engineering to produce gene-targeted rats1,2. The use of somatic cell nuclear transfer to develop cloned rats as an alternative to using embryonic stem cells has also been reported3, but it seems to be a very difficult technique to perform. At present, N-ethyl-N-nitrosourea (ENU) mutagenesis followed by a screening method to detect single-nucleotide substitutions within the targeted gene seems to be the most promising technology in rats, as previously reported by several groups4,5,6. The screening protocol, however, either a yeast-based screening assay4,5 or a high-throughput resequencing-based screening technique7, is expensive. In addition, gene-driven ENU mutagenesis approaches in rats are not a very efficient use of resources because most of the rats generated are usually discarded within a few weeks or months after the targeted genes have been screened owing to a lack of reliable sperm conservation and rederivation technologies.

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Figure 1: Screening assay for ENU-mutagenized rats.

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Acknowledgements

We thank J.L. Guénet for helpful discussion and also thank F. Tagami, T. Yoshida, Y. Kunihiro and S. Nakanishi for experimental support. This study was supported in part by a Grant-in-Aid for Scientific Research (No. 16200029), a Grant-in-Aid for Scientific Research on Priority Areas (No. 18058009) and a Grant-in-Aid for Exploratory Research (No. 19650106) from the Ministry of Education, Culture, Sports, Science and Technology; by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare; by JST in Research for Promoting Technological Seeds (No. 10-037); and by a research grant from the Japan Epilepsy Research Foundation.

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Author notes

  1. Katsuhiko Yanagihara & Reiko Nakajima

    Present address: Present address: Transdisciplinary Research Integration Center, Research Organization of Information and Systems, 411-8540 Mishima, Japan. serikawa@anim.med.kyoto-u.ac.jp,

Authors and Affiliations

  1. Institute of Laboratory Animals, Kyoto University Graduate School of Medicine, Yoshidakonoe-cho, Sakyo-ku, 606-8501, Kyoto, Japan

    Tomoji Mashimo, Satoko Tokuda, Birger Voigt, Akiko Takizawa, Takashi Kuramoto & Tadao Serikawa

  2. Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan

    Katsuhiko Yanagihara & Reiko Nakajima

  3. National Institute for Physiological Sciences, Okazaki, 444-8787, Japan

    Megumi Kato & Masumi Hirabayashi

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2, Supplementary Tables 1–3, Supplementary Methods (PDF 294 kb)

Supplementary Video 1

Intracytoplasmic injection of rat sperm heads with a piezo-driven micromanipulator (MOV 537 kb)

Supplementary Video 2

A phenotype-driven mutant rat that exhibits generalized tonic-clonic seizures (MOV 728 kb)

Supplementary Video 3

A phenotype-driven mutant rat that exhibits abnormal behaviors, such as stress-induced circling (MOV 445 kb)

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Mashimo, T., Yanagihara, K., Tokuda, S. et al. An ENU-induced mutant archive for gene targeting in rats. Nat Genet 40, 514–515 (2008). https://doi.org/10.1038/ng0508-514

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