Genetic regulatory mechanism in development and differentiation

发育和分化的遗传调控机制

• 批准号: 9901590
• 负责人: Paul D Schedl
• 金额: $ 62.11万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901590
• 关键词: Animals; Architecture; Area; Biological Models; Biology; Boundary Elements; Cell Differentiation process; Cell Nucleus; Cell physiology; Cells; Chromatin; Chromosome Structures; Chromosomes; Deposition; Development; Disease; Drosophila genus; Drosophila melanogaster; Elements; Embryo; Etiology; Fertility; Gene Expression Regulation; Genetic; Genetic Transcription; Human Development; Maintenance; Mammals; Memory; Molecular; Pathway interactions; Play; Polycomb; Process; RNA Splicing; Response Elements; Role; Signal Transduction; Site; Somatic Cell; Structure of primordial sex cell; WNT Signaling Pathway; cell fate specification; experimental study; fly; intercellular communication

Project Summary/Abstract Determination of cellular identity is crucial in a variety of developmental frameworks. Fate specification typically involves an initial identity/pathway choice, which can be either deterministic or stochastic. Once selected this identity is reinforced and remembered using mechanisms that are often distinct from those deployed in the initial choice. Lastly, the chosen pathway must be faithfully executed so that cells differentiate appropriately. Over the years, we’ve investigated the process of cell fate specification in several distinct developmental contexts using the genetically tractable fruit fly, Drosophila melanogaster as our model system. Depending on the developmental pathway and the “step” in the specification process (e.g., pathway maintenance) the precise molecular mechanisms needed for proper specification can be at many different levels (cell-cell signaling, transcription, splicing, chromosome structure). In the first part of this proposal we examine the specification of primordial germ cells (PGCs) in the early embryo. In mammals PGC specification depends upon inductive BMP and Wnt signals. In contrast, in multicellular animals other than mammals, PGC specification has long been thought to be a cell-autonomous process that depends upon maternally deposited factors. However, we have recently discovered that BMP signals from somatic cells play an important role in PGC specification in the fly. This discovery suggests that the process of PGC specification across the animal kingdom may be much more similar than previously believed. Our proposed experiments are directed towards understanding the functional coordination between the cell autonomous factors and the BMP pathway during acquisition and maintenance of PGC identity. The second part of the proposal is focused on chromosome architectural elements (boundary elements, Polycomb Response Elements and Chromatin Entry Sites). The proposed experiments will examine how these elements function to determine the topological organization of eukaryotic chromosomes. We will also explore how the activities of these elements impact pathway initiation, memory and execution in several distinct developmental pathways.

项目摘要/摘要 细胞身份的确定在各种发展框架中至关重要。 命运规范通常涉及初始身份/途径选择，可以是 确定性或随机性。一旦选择了这种身份，就会得到加强和记住 使用通常与初始选择中部署的机制不同。最后， 必须忠实地执行所选的途径，以使细胞适当区分。 多年来，我们研究了几个细胞命运规范的过程 使用果蝇果蝇的一般果蝇的不同发育环境 Melanogaster作为我们的模型系统。取决于发展途径和 规范过程中的“步骤”（例如，途径维护）精确分子 正确规格所需的机制可以在许多不同的级别（细胞细胞）处 信号传导，转录，剪接，染色体结构）。在本提案的第一部分 我们检查了早期胚胎中原始生殖细胞（PGC）的规范。在 哺乳动物PGC规范取决于诱导BMP和WNT信号。相比之下， 在哺乳动物以外的多细胞动物中，长期以来一直认为PGC规范 是一个依赖主要沉积因素的细胞自主过程。 但是，我们最近发现，来自体细胞的BMP信号播放 在PGC规范中的重要作用。这一发现表明 整个动物王国的PGC规范可能比以前更相似 相信。我们提出的实验是针对理解功能的 细胞自主因素与BMP途径之间的协调 PGC身份的获取和维护。提案的第二部分集中 关于染色体体系结构元素（边界元素，polycomb响应 元素和染色质输入站点）。提出的实验将研究如何 这些元素功能确定真核的拓扑组织 染色体。我们还将探讨这些元素的活动如何影响途径 在几种不同的发展途径中的启动，记忆和执行。