Lee Jiyoung, Kanatsu-Shinohara Mito, Morimoto Hiroko, Kazuki Yasuhiro, Takashima Seiji, Oshimura Mitsuo, Toyokuni Shinya, Shinohara Takashi
Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Cell Stem Cell. 2009 Jul 2;5(1):76-86. doi: 10.1016/j.stem.2009.04.020.
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.
精原干细胞（SSCs）进行自我更新分裂并支持精子发生。尽管有几种细胞因子协同驱动SSC自我更新，但对于这一过程的潜在机制知之甚少。我们通过在无外源性细胞因子的情况下体外重建SSC自我更新来研究其分子机制。Ras的激活或由Ras诱导的细胞周期蛋白D2和E1的过表达能够使培养的精原细胞进行长期自我更新。具有激活Ras的SSCs对分化信号反应正常并进行精子发生，而在精原细胞移植后，细胞周期蛋白转染细胞中的分化被消除。Ras转染细胞和细胞周期蛋白转染细胞均产生精原细胞瘤，这表明过度的自我更新刺激会诱导致癌转化。相反，过表达细胞周期蛋白D1或D3的细胞在移植后未能形成生殖细胞集落，这表明细胞周期蛋白的表达模式是长期SSC再定殖的重要决定因素。因此，Ras-细胞周期蛋白D2途径调节SSC群体中组织维持与肿瘤发生之间的平衡。
