Stem cell versus meiotic fate decision in C. elegans

摘要 生殖细胞发育的一个关键点是从干/祖细胞到减数分裂和 配子发生。这种发育开关的破坏可能导致不孕不育，在某些情况下会导致生殖系繁殖。 肿瘤。线虫成虫两性体是理解开关控制的重要模型。 生殖系干细胞对减数分裂发育/配子发生的命运，其中控制这一过程的网络是 正在浮现。依赖小生境的GLP-1 Notch信号通过抑制三种方式促进干细胞的命运 促进减数分裂进入的多余转录后途径：GLD-1途径(抑制 有丝分裂周期基因的表达)，GLD-2途径(促进减数分裂基因的表达)，以及 SCFPROM-1途径既降解有丝分裂细胞周期蛋白进入减数分裂阶段，又启动同源 染色体配对。目前的研究表明，虽然转录程序奠定了舞台，但它在很大程度上 执行动物减数分裂进入的转录后调控。在细胞水平上，我们已经在 线虫的干细胞种群很大，生殖细胞直接进入减数分裂，而不干预运输- 扩大分歧。没有传输放大的划分简化了分析，使分析变得简单明了 抑制干细胞减数分裂和抑制有丝分裂细胞周期相关基因的鉴定 进入减数分裂，是线虫成为研究这一重要的重要动物模型的主要原因 发育开关。 这项建议解决了知识方面的三个主要差距和分子/ 线虫干细胞/祖细胞切换到减数分裂发育的生化机制研究。第一, 目前尚不清楚SCFPROM-1在干细胞/祖细胞中是如何被抑制的。第二，GLD-1的信使核糖核酸靶点 抑制有丝分裂周期和促进减数分裂的翻译抑制因子和GLD-2翻译激活因子 基因产物的积累，在很大程度上是未知的。第三，限制GLP-1信号转导的机制 到干细胞生态位区域的作用尚不完全清楚，以及mET-10m6A 甲基转移酶抑制GLP-1信号转导尚不清楚。自交系的分子/生化研究 干细胞/祖细胞进入减数分裂受到线虫种系的限制，该种系包含所有阶段，存在于 从干细胞到成熟配子的流水线顺序，在任何给定的阶段都占很小的比例。我们会 开发一种从干细胞同步切换到减数分裂进入的遗传系统，在足够大的 生殖细胞和动物种群，以进行分子/生化研究。

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.