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The Novel Dominant Mutation Dspd Leads to a Severe Spermiogenesis Defect in Mice¹

Division for Gene Research,⁴ Center for Biological Resources and Informatics, Tokyo Institute of Technology, Midori-ku, Yokohama 226-8501, Japan CREST,⁵ Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0011, Japan BioResource Center,⁶ RIKEN, Tsukuba, Ibaraki 305-0074, Japan Mitsubishi Kagaku Institute of Life Sciences,⁷, Tokyo 194-8511, Japan Central Institute for Experimental Animals,⁸ Miyamae-ku, Kawasaki 216-0001, Japan Exploratory Toxicology and DMPK Research Laboratories,⁹ Tanabe Seiyaku Co., Ltd., Chuo-ku, Osaka 541-8505, Japan School of Health Sciences,¹⁰ Tokai University, Bohseidai, Isehara, Kanagawa 259-11, Japan Medical Research Institute,¹¹ Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan

Spermiogenesis is a complex process that is regulated by a plethora of genes and interactions between germ and somatic cells. Here we report a novel mutant mouse strain that carries a transgene insertional/translocational mutation and exhibits dominant male sterility. We named the mutation dominant spermiogenesis defect (Dspd). In the testes of Dspd mutant mice, spermatids detached from the seminiferous epithelium at different steps of the differentiation process before the completion of spermiogenesis. Microinsemination using spermatids collected from the mutant testes resulted in the birth of normal offspring. These observations indicate that the major cause of Dspd infertility is (are) a defect(s) in the Sertoli cell-spermatid interaction or communication in the seminiferous tubules. Fluorescent in situ hybridization (FISH) analysis revealed a translocation between chromosomes 7F and 14C at the transgene insertion site. The deletion of a genomic region of chromosome 7F greater than 1 megabase and containing at least six genes (Cttn, Fadd, Fgf3, Fgf4, Fgf15, and Ccnd1) was associated with the translocation. Cttn encodes the actin-binding protein cortactin. Immunohistochemical analysis revealed localization of cortactin beside elongated spermatids in wild-type testes; abnormality of cortactin localization was found in mutant testes. These data suggest an important role of cortactin in Sertoli cell-spermatid interactions and in the Dspd phenotype.

¹ This work was supported by grants to F.I. from CREST, the research program of the Japan Science and Technology Agency (JST), the Uehara Memorial Life Science Foundation, and the Ministry of Health, Labour for Child Health and Development (14-C).

² Correspondence: Fumitoshi Ishino, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan. FAX: +81 3 5280 8073; fishino.epgn{at}mri.tmd.ac.jp

³ Current address: Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-8681, Japan

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