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HST-1/FGF-4 gene activation induces spermatogenesis and prevents adriamycin-induced testicular toxicity

Oncogene volume 21, pages 899–908 (2002)Cite this article

Abstract

We previously demonstrated expression of the HST-1/FGF-4 gene in the testis of normal adult animals, which suggests its possible role in spermatogenesis. For an understanding of its functional significance in the testis, conditional transgene expression was used. Precise genetic switches can be efficiently generated in a straightforward manner using adenovirus-carrying Cre recombinase, which means our new strategies promise to contribute substantially to a better and prompt understanding of the functions of genes in vivo by controlling the expression of any gene to any organ at any desired time. Our new method demonstrated for the first time that the specific gain of function of the HST-1/FGF-4 gene in the testis resulted in markedly enhanced spermatogenesis. To further investigate the function and therapeutic potency of HST-1/FGF-4, transgenic mice with enhanced HST-1/FGF-4 expression in the testis were exposed to adriamycin (ADR), an anticancer drug causing severe testicular toxicity. Degree of damage to spermatogenesis was assessed by sperm count, testicular weight, histology, and DNA ploidy. Induced expression of HST-1/FGF-4 markedly enhanced the recovery of ADR-induced testicular damage. Furthermore, adenoviruses carrying the HST-1/FGF-4 gene ameliorated testicular toxicity of ADR. These results with new adenovirus-mediated Cre/lox conditional mice indicated that HST-1/FGF-4 could be an important factor for spermatogenesis, presenting a new paradigm to treat impaired fertility.

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Acknowledgements

We gratefully thank Dr Junichi Miyazaki (Osaka University, Japan) for his kind gift of CAG promoter. We thank Ms Maki Abe and Ms Masako Hosoda for their excellent technical work. This work was supported in part by a Grant-in-Aid for the Second-Term Comprehensive 10-Year Strategy for Cancer Control, Health Science Research Grants for the Research on Human Genome and Gene Therapy from the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-Aid by Japan Owner's Association.

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Authors and Affiliations

  1. Section for Studies on Metastasis, National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, Tokyo, 104-0045, Japan

    Hanako Yamamoto, Takahiro Ochiya, Kotaro Hirai & Hideo Sasaki

  2. Chemotherapy Division, National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, Tokyo, 104-0045, Japan

    Hiroyasu Toriyama-Baba

  3. Genetics Division, National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, Tokyo, 104-0045, Japan

    Hiromi Sakamoto & Masaaki Terada

  4. National Cancer Center Hospital, National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, Tokyo, 104-0045, Japan

    Tadao Kakizoe

  5. CLEA Japan. Inc., 983-5, Kami-Yuzuno, Fuji, Shizuoka, 419-0301, Japan

    Shoujiro Tamamushi

  6. First Department of Surgery, Nara Medical University, Nara, 634-8522, Japan

    Yasushi Takahama

  7. Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, 4-6-1, Shiroganedai, Minato-ku, Tokyo, 108-8639, Japan

    Izumu Saito

  8. Department of Urology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-kuk, Kawasaki, 216-8511, Japan

    Teruaki Iwamoto

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  1. Hanako Yamamoto
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  12. Masaaki Terada
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Correspondence to Masaaki Terada.

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Yamamoto, H., Ochiya, T., Tamamushi, S. et al. HST-1/FGF-4 gene activation induces spermatogenesis and prevents adriamycin-induced testicular toxicity. Oncogene 21, 899–908 (2002). https://doi.org/10.1038/sj.onc.1205135

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