P granules and control of germ cell development

摘要 生殖细胞执行多细胞生物体的生殖功能，而正常生殖细胞 发展确保了物种的生存。胚芽颗粒是胚芽中保守的细胞器。 细胞，对这些细胞的生存、分化和功能是必不可少的。胚芽颗粒成分的突变 或它们的表达缺失会导致模式生物的不孕，并与人类的不孕不育有关。通过 相比之下，体细胞中生殖细胞颗粒成分的不适当表达与癌症的发生有关 人类。在胚芽中发现了许多rna结合蛋白和发育调节的mrna。 颗粒，导致了一种假设，即这些细胞器在调节mRNA稳定性或翻译 活性；然而，这些细胞器的分子功能仍然不确定。 线虫线虫已被用于分析种系中的mRNA翻译控制 发展。通过关注促进RNA结合调节蛋白FBF-2本地化的辅助因素 对于生殖系干细胞中的生殖粒(在这个物种中称为P颗粒)，我们已经产生了一组 将解决P颗粒调节FBF-2活性的关键机制的创新工具。通过 结合基于遗传、分子、生化和成像的方法，我们将：1)确定FBF-2如何 与P颗粒定位重要的辅因子蛋白DLC-1的相互作用影响翻译抑制 FBF-2的作用；2)确定了P颗粒重塑的机制，这些重塑在 干细胞从增殖到分化时开始减数分裂；3)确定DLC-1的作用 与核心P颗粒成分结合对胚胎P颗粒稳定性的调节及对P颗粒募集的影响 瞬时P颗粒成分如FBF-2到成体生殖系P颗粒。我们的实验系统是 准备揭示特定的分子机制，介导细菌颗粒和 翻译法规。由于细菌颗粒是保守的细胞器，我们的研究重点是 保守的调节蛋白，在这个模型系统中的研究将提供关键的洞察力的原因 人类的不孕不育。

Abstract Germ cells carry out the reproductive function of multicellular organisms, and normal germ cell development ensures survival of the species. Germ granules are conserved cytoplasmic organelles of germ cells, essential for survival, differentiation, and function of these cells. Mutations in germ granule components or loss of their expression lead to infertility in model organisms and are associated with infertility in humans. By contrast, inappropriate expression of germ granule components in somatic cells is linked to carcinogenesis in humans. Many RNA-binding proteins and developmentally regulated mRNAs are found enriched in germ granules, leading to a hypothesis that these organelles function in regulation of mRNA stability or translational activity; yet, the molecular function of these organelles is still undefined. The nematode C. elegans has been instrumental for analysis of mRNA translational control in germline development. Through focusing on cofactors that promote localization of RNA-binding regulatory protein FBF-2 to germ granules (called P granules in this species) in germline stem cells we have generated a set of innovative tools that will address key mechanisms through which P granules regulate FBF-2 activity. By integrating genetic, molecular, biochemical and imaging-based approaches, we will: 1) Determine how FBF-2 interaction with a cofactor protein DLC-1 important for P granule localization impacts translational repression exerted by FBF-2; 2) Define the mechanisms of P granule remodeling that specifically degrade FBF-2 at the onset of meiosis when stem cells transition from proliferation to differentiation; 3) Determine the role of DLC-1 binding to core P granule components in regulation of stability of embryonic P granules and in recruitment of transient P granule components such as FBF-2 to adult germline P granules. Our experimental system is poised to reveal specific molecular mechanisms mediating the interplay between germ granules and translational regulation. Since germ granules are conserved organelles and our research focuses on conserved regulatory proteins, studies in this model system will provide critical insight into the causes of infertility in humans.