title: Genetic reconstruction of mouse spermatogonial stem cell self-renewal in vitro by Ras-cyclin D2 activation.
abstract: Spermatogonial stem cells (SSCs) undergo self-renewal division and support spermatogenesis. Although several cytokines coordinate to drive SSC self-renewal, little is known about the mechanisms underlying this process. We investigated the molecular mechanism by reconstructing SSC self-renewal in vitro without exogenous cytokines. Activation of Ras or overexpression of cyclins D2 and E1, both of which were induced by Ras, enabled long-term self-renewal of cultured spermatogonia. SSCs with activated Ras responded properly to differentiation signals and underwent spermatogenesis, whereas differentiation was abrogated in cyclin transfectants after spermatogonial transplantation. Both Ras- and cyclin-transfected cells produced seminomatous tumors, suggesting that excessive self-renewing stimulus induces oncogenic transformation. In contrast, cells that overexpressed cyclin D1 or D3 failed to make germ cell colonies after transplantation, which indicated that cyclin expression pattern is an important determinant to long-term SSC recolonization. Thus, the Ras-cyclin D2 pathway regulates the balance between tissue maintenance and tumorigenesis in the SSC population.
authors: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors: Jiyoung
authors: J
authors: Lee
authors: Mito
authors: M
authors: Kanatsu-Shinohara
authors: Hiroko
authors: H
authors: Morimoto
authors: Yasuhiro
authors: Y
authors: Kazuki
authors: Seiji
authors: S
authors: Takashima
authors: Mitsuo
authors: M
authors: Oshimura
authors: Shinya
authors: S
authors: Toyokuni
authors: Takashi
authors: T
authors: Shinohara
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D011905:Genes, ras / Q000502:physiology; D008297:Male; D051379:Mice; D013093:Spermatogonia / Q000166:cytology* / Q000254:growth & development; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics; D013737:Testis / Q000166:cytology / Q000378:metabolism; D014162:Transfection; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D016207:Cytokines; D018631:ras Proteins