REGULATION AND FUNCTION OF THE STEM SPERMATOGONIA NICHE

雄配子的持续产生需要精确地调节分化和 茎精原细胞的复制。这些关键过程发生在一个动态环境中 部分由支持细胞产生，支持细胞是所有生精细胞相互作用的体细胞。到目前为止，In 支持细胞调节干细胞精原分化和复制的体内机制尚未见报道 已被阐明。也不知道支持细胞的这些调节功能是如何自身发挥的 控制住了。这一应用的中心假设是分化的生精细胞控制着 支持细胞表达调控干细胞分化和复制的生长因子 精原细胞。我们认为，通过调节这些生长因子的表达，分化 生精细胞控制着干细胞精原细胞的功能。以小鼠为模型，这是 建议集中在三种生长因子上，这三种生长因子被证明可以刺激干细胞精原细胞的生长 无论是在体内还是在体外。这些生长因子是：胶质细胞源性神经营养因子(GDNF)， 成纤维细胞生长因子2(FGF-2)和胰岛素样生长因子1(IGF-1)。《特定目标I》检验这个假设 在体内，支持细胞阶段特异性表达GDNF调节肿瘤细胞的复制和分化 干细胞精原细胞及成纤维细胞生长因子-2、胰岛素样生长因子-1与胶质细胞源性神经营养因子的协同调节作用 流程。特殊目的II检验A1型精原细胞或更高级的假设 生精细胞调节支持细胞表达GDNF、FGF-2和IGF-1。要开始定义 这一调控的分子基础，我们还建议无偏见地寻找转录因子和 生精细胞对胶质细胞源性神经营养因子影响的信号转导途径 支持细胞表达。《特定目标III》将检验这样一种假设，即通过 它们对支持细胞的反馈控制着干细胞精原细胞的更新和分化。阶段特异性基因 Sertoli细胞的表达在许多物种中都是一种公认的现象，包括人类和GDNF， 胰岛素样生长因子-1和成纤维细胞生长因子-2在人类睾丸中均有表达。因此，我们提议的实验结果成立 承诺了解某些男性不育症的生物学基础。

The continuous production of male gametes requires the precise regulation of the differentiation and replication of stem spermatogonia. These critical processes occur in a niche that is a dynamic environment created in part by Sertoli cells, the somatic cells with which all spermatogenic cells interact. As yet, the in vivo mechanisms by which Sertoli cells regulate stem spermatogonial differentiation and replication have not been elucidated. Neither is it understood how those regulatory functions of Sertoli cells are themselves controlled. The central hypothesis of this application is that differentiated spermatogenic cells control the expression by Sertoli cells of growth factors that regulate the differentiation and replication of stem spermatogonia. We propose that by regulating expression of those growth factors, differentiated spermatogenic cells control the functioning of the stem spermatogonia niche. Using mice as a model, this proposal focuses on three growth factors that been shown to stimulate the growth of stem spermatogonia either in vivo or in vitro. These growth factors are: glial cell line derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF-2) and insulin like growth factor 1 (IGF-1). Specific Aim I tests the hypothesis that in vivo the stage-specific expression of GDNF by Sertoli cells regulates replication and differentiation of stem spermatogonia and that FGF-2 and IGF-1 act in consort with GDNF in the regulation of these processes. Specific Aim II tests the hypothesis that Type A1 spermatogonia or more advanced spermatogenic cells regulate expression of GDNF, FGF-2 and IGF-1 by Sertoli cells. To begin to define the molecular basis of this regulation, we also propose an unbiased search for transcription factors and components of signal transduction pathways that mediate the effects of spermatogenic cells on GDNF expression by Sertoli cells. Specific Aim III will test the hypothesis that differentiated spermatogenic cells by their feedback on Sertoli cells control stem spermatogonia renewal and differentiation. Stage-specific gene expression by Sertoli cells is a well-established phenomenon in many species, including humans and GDNF, IGF-1 and FGF-2 are all expressed in human testes. Therefore, results from our proposed experiments hold promise for understanding the biological basis of the infertility of some men.