Investigating the signaling mechanisms required for germ cell differentiation

描述(申请人提供)：卵子和精子的正常发育是大多数动物繁殖所必需的。因此，原始生殖细胞规格，即保留产生卵子和精子的细胞，是动物发育过程中未来繁殖成功的关键时期。在小鼠和人类中，发育过程中需要细胞间信号来诱导生殖细胞分化，而苍蝇和蠕虫则使用一种独特的、母系获得的机制来确定它们的生殖细胞。该项目的长期目标是了解限制生殖细胞诱导信号的准确诱导信号和分子机制，并确定这些机制如何有助于生殖细胞命运的正确分化。小鼠和海星都需要结节信号来增强限制其成为生殖细胞的潜能的发育轴。我们假设Nodal信号限制了可以成为生殖细胞的细胞数量。我们将通过干扰Nodal信号并确定导致生殖细胞规格的mRNAs负积累的确切分子机制来严格检验这一假说。此外，我们将定义建立生殖细胞规范所需的形态发生细胞表型，并确定Nodal信号如何抑制细胞呈现这些形态发生细胞特征。这些结果将是补充的，并被整合到哺乳动物生殖细胞诱导的模型中，但这项研究的目的是使用一种易于处理的有机体进行细胞和生化方法。对调控生殖细胞命运分化的精确分子机制的深入了解，对于确定涉及以下方面的新基因至关重要：不孕不育的遗传基础，威胁生命的畸胎瘤的诱导，以及带有上调的生殖细胞相关基因的癌症的增殖能力。

DESCRIPTION (provided by applicant): The proper development of eggs and sperm is required for most animal reproduction. As such, primordial germ cell specification, the setting aside of the cells that give rise to eggs and sperm, is a crucial time in animal development for future reproductive success. In mice and humans, intercellular signals are required to induce germ cell differentiation during development, whereas flies and worms use a distinct, maternally-acquired mechanism to determine their germ cells. The long-term goal of this project is to understand the precise inductive signaling and molecular mechanisms that restrict the germ-cell inducing signals and to determine how these mechanisms contribute to the proper differentiation of the germ cell fate. Nodal signaling is required in both mice and sea stars to se up the developmental axes that restrict the potential to become germ cells. We hypothesize that Nodal signaling restricts the population of cells that can become germ cells. We will rigorously test this hypothesis by perturbing Nodal signaling and determining the precise molecular mechanisms that contribute to the negative accumulation of mRNAs for germ cell specification. In addition, we will define the morphogenetic cellular phenotypes required for the establishment of a germ cell specification niche and determine how Nodal signaling inhibits cells from taking on these morphogenetic cellular traits. These results will be complementary, and integrated into, models of mammalian germ cell induction, but the purpose of this research is to use an organism tractable for cellular and biochemical approaches. Insights into the precise molecular mechanisms that regulate the differentiation of the germ cell fate are crucial to identify novel genes involved in: the genetic basis of infertility, the induction of life-threatening teratomas, ad the proliferative abilities of cancers with upregulated germ-cell associated genes.