REGULATION AND FUNCTION OF THE STEM SPERMATOGONIA NICHE

雄配子的连续产生需要精确调节细胞的分化和分化。 干精原细胞的复制。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，在 支持细胞调节干精原细胞分化和复制的体内机制还没有 被阐明。支持细胞的这些调节功能本身也不清楚 控制。本申请的中心假设是，分化的生精细胞控制着精子的发育。 支持细胞表达调节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 生精细胞控制着干精原细胞龛的功能。以老鼠为模型， 一项提案集中在三种已被证明能刺激干精原细胞生长的生长因子上 无论是在体内还是体外。这些生长因子是：胶质细胞系衍生的神经营养因子（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）。具体目标I检验假设 在体内，支持细胞的GDNF阶段特异性表达调节了细胞的复制和分化。 干精原细胞和FGF-2和IGF-1与GDNF一起在这些调节中起作用 流程.特异性目的II检验了A1型精原细胞或更高级精原细胞的假设， 生精细胞通过支持细胞调节GDNF、FGF-2和IGF-1的表达。开始定义 这种调节的分子基础，我们还提出了一个公正的搜索转录因子， 介导生精细胞对GDNF作用的信号转导通路组分 支持细胞的表达。具体目标III将检验以下假设： 它们对支持细胞的反馈控制着干精原细胞的更新和分化。期特异性基因 支持细胞的表达在许多物种中是一种公认的现象，包括人和GDNF， IGF-1和FGF-2均在人睾丸中表达。因此，我们提出的实验结果成立 希望能帮助我们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.