Proliferation and differentiation of spermatogonial stem cells in the w/wv mutant mouse testis.
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/Wv mutant mouse testis. In the present study, some of the W/Wv mutant testes completely lacked spermatogonia, and many of the remaining testes contained only a few spermatogonia. Examination of the proliferative activity of the W/Wv mutant spermatogonia by transplantation of enhanced green fluorescent protein (eGFP)-labeled W/Wv spermatogonia into the seminiferous tubules of normal SCF (W/Wv) or SCF mutant (Sl/Sld) mice demonstrated that the W/Wv 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/Wv 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/Wv 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.
Ohta
Hiroshi
H
Department of Science for Laboratory Animal Experimentation, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan.
Tohda
Akira
A
Nishimune
Yoshitake
Y
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D017690:Cell Transplantation / Q000379:methods; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D013093:Spermatogonia / Q000187:drug effects / Q000473:pathology* / Q000637:transplantation; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000473:pathology; D013737:Testis / Q000473:pathology*
D008164:Luminescent Proteins; D019089:Stem Cell Factor; D049452:Green Fluorescent Proteins; D007987:Gonadotropin-Releasing Hormone; D019009:Proto-Oncogene Proteins c-kit