Zinc Regulation of Germline and Embryo Development in Caenorhabditis elegans

描述（由申请人提供）：锌是一种过渡金属，在一系列细胞过程中起作用，传统上被认为是辅助因子和结构调节剂。我们提出了一个新的和前所未有的作用，锌作为调节无机细胞信号。O'Halloran和Woodruff实验室的研究表明，锌通过大量的锌通量和锌与锌指结合蛋白Emi2的关联来调节小鼠卵母细胞的减数分裂进程。锌是细胞周期进程的主要调节剂，这一发现有可能广泛影响人类疾病的研究，因为我们细胞中存在的极端水平的锌会对细胞分裂产生负面影响。我们正在扩大对秀丽隐杆线虫的研究，以利用它们的生殖寿命短，后代数量多和半透明。目前尚不清楚在秀丽隐杆线虫中锌主调控是否是一个保守的细胞信号传导机制。因此，提出的目标将填补这一知识空白，并确定锌如何调节细胞信号通路定义发育中的种系。为了实现这一目标，我们将量化性腺内的总锌和不稳定锌，测试锌转换事件的机制，以确定性腺的不同区域，并确定锌主控Notch信号通路的分子机制。与对照组相比，这些实验将在缺锌条件下进行。从这些研究中获得的信息将推进锌作为细胞信号调节剂的知识基础，并进一步了解锌如何调节细胞周期和生殖细胞身份，这对新后代的发育至关重要。

DESCRIPTION (provided by applicant): Zinc is a transition metal that plays a role in an array of cellular processes and has traditionally been considered a cofactor and structural regulator. We propose a novel and unprecedented role for zinc as regulator in inorganic cell signaling. Studies from the O'Halloran and Woodruff labs have demonstrated that zinc regulates meiotic progression in mouse oocytes through massive zinc fluxes and association of zinc with the zinc-finger binding protein Emi2. The discovery that zinc is a master regulator of cell cycle progression has the potential to broadly impact the study of human disease, as extreme levels of zinc present in our cells can negatively affect cell division. We are expanding studies into Caenorhabditis elegans, to exploit their short reproductive lifespan, high number of offspring and translucence. It is unknown if zinc master regulation is a conserved cell signaling mechanism in C. elegans. Therefore, the proposed aims will fill this knowledge gap and identify how the zinc regulated cell signaling pathway defines the developing germline. We will achieve this goal by quantifying total and labile zinc within the gonad, test mechanisms of zinc switching events to define different regions of the gonad and identify the molecular mechanism of master zinc regulation of the Notch signaling pathway. These experiments will be conducted under zinc deficient conditions compared to controls. Information acquired from these studies will advance the knowledge base in zinc as a cell signaling regulator and lead to further understanding how zinc regulates cell cycle and thus germ cell identity, which is crucial for the development of new offspring.