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Proliferation and Differentiation of Spermatogonial Stem Cells in the W/W^v Mutant Mouse Testis¹

Department of Science for Laboratory Animal Experimentation,⁴ Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan Department of Urology,⁵ Osaka University Medical School, Osaka, 565-0871, Japan

Mutations in the dominant-white spotting (W; c-kit) and stem cell factor (Sl; SCF) genes, which encode the transmembrane tyrosine kinase receptor and its ligand, respectively, affect both the proliferation and differentiation of many types of stem cells. Almost all homozygous W or Sl mutant mice are sterile because of the lack of differentiated germ cells or spermatogonial stem cells. To characterize spermatogenesis in c-kit/SCF mutants and to understand the role of c-kit signal transduction in spermatogonial stem cells, the existence, proliferation, and differentiation of spermatogonia were examined in the W/W^v mutant mouse testis. In the present study, some of the W/W^v mutant testes completely lacked spermatogonia, and many of the remaining testes contained only a few spermatogonia. Examination of the proliferative activity of the W/W^v mutant spermatogonia by transplantation of enhanced green fluorescent protein (eGFP)-labeled W/W^v spermatogonia into the seminiferous tubules of normal SCF (W/W^v) or SCF mutant (Sl/Sl^d) mice demonstrated that the W/W^v spermatogonia had the ability to settle and proliferate, but not to differentiate, in the recipient seminiferous tubules. Although the germ cells in the adult W/W^v testis were c-kit-receptor protein-negative undifferentiated type A spermatogonia, the juvenile germ cells were able to differentiate into spermatogonia that expressed the c-kit-receptor protein. Furthermore, differentiated germ cells with the c-kit-receptor protein on the cell surface could be induced by GnRH antagonist treatment, even in the adult W/W^v testis. These results indicate that all the spermatogonial stem cell characteristics of settlement, proliferation, and differentiation can be demonstrated without stimulating the c-kit-receptor signal. The c-kit/SCF signal transduction system appears to be necessary for the maintenance and proliferation of differentiated c-kit receptor-positive spermatogonia but not for the initial step of spermatogonial cell differentiation.

¹ H.O. is the recipient of a Research Fellowship of the Japan Society for the Promotion of Science (2000–2003). Nal-Glu was synthesized at the Salk Institute (under contract NO1-HD-0-2906 with the NIH) and kindly provided by the Contraception and Reproductive Health Branch, Center for Population Research, NICHD.

² Correspondence: Yoshitake Nishimune, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita, Osaka, Japan 565-0871. FAX: 81 6 6879 8339; nishimun{at}biken.osaka-u.ac.jp

³ Current address: Laboratory for Genomic Reprogramming, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan

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