Stem cell versus meiotic fate decision in C. elegans

摘要 生殖细胞发育的关键点是从干/祖细胞到减数分裂的转变， 配子发生这种发育开关的中断可能导致不育，在某些情况下， 肿瘤的梭秀丽线虫的雌雄同体是一个重要的模型，用于理解控制开关， 生殖系干细胞命运减数分裂发育/配子发生，其中控制该过程的网络是 正在浮现小生境依赖性GLP-1 Notch信号通过抑制三种细胞因子促进干细胞命运 促进减数分裂进入的冗余转录后途径：GLD-1途径（抑制 有丝分裂周期基因的表达）、GLD-2途径（其促进减数分裂基因的表达），以及 SCFPROM-1途径既降解减数分裂进入时的有丝分裂细胞周期蛋白，又启动同源 染色体配对目前的研究表明，虽然转录程序设置的阶段，它在很大程度上是 在动物中执行减数分裂进入的转录后调节。在细胞水平上，我们已经证明， C.干细胞群体很大，生殖细胞直接进入减数分裂，没有干预的过境， 扩大分歧没有过渡放大的部门简化了分析， 鉴定干细胞减数分裂抑制和有丝分裂细胞周期抑制相关基因的试验 减数分裂进入，是C.秀丽线虫是研究这一重要生物的主要动物模型。 发育开关 该提案涉及分子/生物技术领域的三大知识差距和一项重大技术挑战。 C.干细胞/祖细胞转换到减数分裂发育的生化机制研究优雅第一、 尚不清楚SCFPROM-1在干/祖细胞中是如何被抑制的。第二，GLD-1的mRNA靶点 翻译抑制因子和GLD-2翻译激活因子，它们抑制有丝分裂周期并促进减数分裂 基因产物的积累，在很大程度上是未知的。第三，GLP-1信号传导受到限制的机制 干细胞生态位区域的机制尚不完全清楚，mett-10 m6 A 甲基转移酶抑制GLP-1信号传导的研究尚未描述。分子/生物化学研究的开关从 干/祖细胞进入减数分裂受C.秀丽隐杆线虫种系包含所有阶段，存在于 从干细胞到成熟配子的装配线顺序，任何给定的阶段都只占很小的比例。我们将 开发一个遗传系统，从干细胞同步开关到减数分裂进入，在足够大的 生殖细胞和动物群体，以便进行分子/生物化学研究。

Abstract A key point in germ cell development is the switch from stem/progenitor cells to meiosis and gametogenesis. Disruption of this developmental switch can result in infertility and in some cases germline tumors. The C. elegans adult hermaphrodite is an important model for understanding control of the switch from germline stem cell fate to meiotic development/gametogenesis, where a network controlling the process is emerging. Niche dependent GLP-1 Notch signaling promotes the stem cell fate through repressing three redundant posttranscriptional pathways that promote meiotic entry: the GLD-1 pathway (which represses expression of mitotic cycling genes), the GLD-2 pathway (which promotes expression of meiotic genes), and the SCFPROM-1 pathway that both degrades mitotic cell cycle proteins at meiotic entry and initiates homologous chromosome pairing. Current studies indicate that while transcriptional programs set the stage, it is largely posttranscriptional regulation that executes meiotic entry in animals. At a cellular level, we have shown that in C. elegans the stem cell population is large and germ cells enter meiosis directly, without intervening transit- amplifying divisions. The absence of transit-amplifying divisions simplifies the analysis allowing straightforward assays to identify genes involved in repressing meiosis in stem cells and repressing mitotic cell cycling at meiotic entry and is the primary reason why C. elegans is a major animal model for studying this important developmental switch. This proposal addresses three major gaps in knowledge and a major technical challenge in molecular/ biochemical mechanistic studies of the stem cell/progenitor switch to meiotic development in C. elegans. First, it is not known how SCFPROM-1 is repressed in stem/progenitor cells. Second, the mRNA targets of the GLD-1 translational repressor and the GLD-2 translational activator, which repress mitotic cycling and promote meiotic gene product accumulation, are largely unidentified. Third, mechanisms by which GLP-1 signaling is restricted to the stem cell niche region are not fully known, and the mechanism by which the mett-10 m6A methyltransferase inhibits GLP-1 signaling is undescribed. Molecular/biochemical studies of the switch from stem/progenitor cells to meiotic entry are limited by the C. elegans germline containing all stages, present in an assembly-line order from stem cells to mature gametes, with any given stage a small proportion. We will develop a genetic system for the synchronous switch from stem cells to meiotic entry, in a sufficiently large population of germ cells and animals to allow molecular/biochemical studies.