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.

项目总结/摘要 细胞身份的确定在各种发育框架中至关重要。 命运规范通常涉及初始身份/途径选择，其可以是 确定性或随机性。一旦被选中，这个身份就会被强化和记住。 使用的机制通常与最初的选择不同。最后， 必须忠实地执行所选择的途径，以便细胞适当地分化。 多年来，我们已经研究了几个细胞命运特化的过程， 不同的发展背景下使用遗传上易处理的果蝇， melanogaster作为模型系统。根据发育途径和 规范过程中的“步骤”（例如，通路维持）的精确分子 适当规范所需的机制可以处于许多不同的级别（单元-单元 信号传导、转录、剪接、染色体结构）。在本提案的第一部分， 我们研究了早期胚胎中原始生殖细胞（PGCs）的特化。在 哺乳动物PGC特异性依赖于诱导性BMP和Wnt信号。与此相反， 在哺乳动物以外的多细胞动物中，PGC特化长期以来被认为 这是一个细胞自主的过程，依赖于母体沉积的因子。 然而，我们最近发现，来自体细胞的BMP信号发挥着重要作用。 PGC规范中的重要作用。这一发现表明， 整个动物王国的PGC规格可能比以前更加相似 相信。我们提出的实验旨在了解功能性 细胞自主因子和BMP通路之间的协调， 获取和维护PGC身份。建议书的第二部分是重点 染色体结构元件（边界元件，Polycomb响应 元素和染色质进入位点）。拟议的实验将研究如何 这些元件的功能是决定真核生物的拓扑结构 染色体我们还将探讨这些元素的活动如何影响途径 启动，记忆和执行在几个不同的发展途径。