Investigating the signaling mechanisms required for germ cell differentiation

研究生殖细胞分化所需的信号传导机制

• 批准号: 8911175
• 负责人: Tara Micole Fresques
• 金额: $ 4.31万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911175
• 关键词: Affect; Ambystoma; Animals; BMP4; Biochemical; Cell Differentiation process; Cells; Data; Derivation procedure; Development; Dorsal; Down-Regulation; Embryo; Embryonic Structures; Endoderm; Event; Future; Gastrula; Genes; Genetic; Genomics; Germ Cells; Goals; Gryllidae; Human; Human body; Infertility; Lead; Left; Life; Ligands; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Molecular Target; Morphogenesis; Mus; Nodal; Organism; Phenotype; Population; Process; Regulation; Reproduction; Research; Resources; Shapes; Side; Signal Transduction; Somatic Cell; Staging; Starfish; Sterility; Structure; Structure of primordial sex cell; System; Teratoma; Testing; Time; To specify; Translations; Visceral; Zebrafish; base; blastomere structure; design; egg; fly; gastrulation; gene therapy; insight; next generation; novel; precursor cell; programs; public health relevance; reproductive success; research study; sperm cell; therapy design; trait

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.

描述（由申请人提供）：大多数动物繁殖都需要卵子和精子的正常发育。因此，原始生殖细胞规范，即产生卵子和精子的细胞，是动物发育中未来生殖成功的关键时刻。在小鼠和人类中，细胞间信号需要在发育过程中诱导生殖细胞分化，而苍蝇和蠕虫则使用一种独特的、母体获得的机制来决定它们的生殖细胞。本项目的长期目标是了解生殖细胞诱导信号的精确诱导信号和限制生殖细胞诱导信号的分子机制，并确定这些机制如何促进生殖细胞命运的正确分化。在小鼠和海星中都需要节点信号来激活限制成为生殖细胞潜能的发育轴。我们假设节点信号限制了可以成为生殖细胞的细胞数量。我们将通过干扰节点信号并确定导致mrna负积累的精确分子机制来严格验证这一假设。此外，我们将定义建立生殖细胞特定生态位所需的形态发生细胞表型，并确定节点信号如何抑制细胞承担这些形态发生细胞特征。这些结果将补充并整合到哺乳动物生殖细胞诱导模型中，但本研究的目的是使用可用于细胞和生化方法的生物体。深入了解调节生殖细胞命运分化的精确分子机制，对于识别涉及以下方面的新基因至关重要：不育的遗传基础，危及生命的畸胎瘤的诱导，以及与生殖细胞相关基因上调的癌症的增殖能力。