Genetic regulatory mechanism in development and differentiation

项目摘要/摘要 细胞身份的确定在各种发育框架中是至关重要的。 命运规范通常涉及初始身份/路径选择，它可以是 确定性的或随机的。一旦被选中，这个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的机制。最后， 选择的途径必须忠实地执行，这样细胞才能适当分化。 多年来，我们在几个方面研究了细胞命运指定的过程 利用遗传易驯化的果蝇果蝇的不同发育背景 黑作为我们的模型系统。取决于发育途径和 在特化过程中(例如，通路维护)，精确的分子 适当规范所需的机制可以在许多不同的级别(单元-单元 信号、转录、剪接、染色体结构)。在本提案的第一部分中 我们研究了早期胚胎中原始生殖细胞(PGC)的规格。在……里面 哺乳动物PGC的特性取决于诱导性BMP和WNT信号。相比之下， 在哺乳动物以外的多细胞动物中，PGC规范一直被认为是 是一个细胞自主的过程，取决于母体沉积的因素。 然而，我们最近发现，来自体细胞的BMP信号发挥着 在PGC规范中扮演重要角色。这一发现表明，这一过程 整个动物界的PGC规范可能比以前更相似 相信。我们提议的实验是为了理解功能 细胞自主因子与骨形态发生蛋白途径的协同作用 获取和维护PGC身份。提案的第二部分是重点 关于染色体构筑元素(边界元素、多梳响应 元素和染色质进入位点)。拟议中的实验将检验如何 这些元件决定了真核生物的拓扑结构 染色体。我们还将探索这些元素的活动如何影响通路 在几个不同的发育过程中的启动、记忆和执行。

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.