Bridging Dynamic Signaling and Somite Morphogenesis

描述（由申请人提供）：体节发生是一个动态过程，其将整体和局部信号传导与细胞形态发生整合，以沿着脊椎动物胚胎的轴沿着产生有序排列的同色异谱单位或体节。本项目的目标是了解Notch，Fgf，Wnt和视黄酸通路的读出如何结合在一起，影响原钙粘蛋白介导的细胞行为在体节边界形成。一个非洲爪蟾外植体系统将开发可视化的行为，在正常和实验条件下的前或后体节隔室。一种新的原钙粘蛋白，近轴原钙粘蛋白2（PAPC 2），在建立细胞间相互作用的体节边界的变化的作用将使用这个外植体系统进行检查。最后，控制PAPC2表达的增强子区域在形成体节边界将被分离，以进一步了解如何输入的信号在前体中胚层的位置表达的基因，在边界形成的作用。在癌性肿瘤生长和转移期间观察到原钙粘蛋白表达的变化以及Wnt、Fgf、Notch和视黄酸信号传导途径的失调。了解这些途径在发育过程中整合以改变细胞行为的方式将为创建知情模型提供强有力的实验证据，这将有助于阐明这些信号通路在疾病进展中的作用。许多导致肿瘤生长和形成的基因也与胚胎的早期发育有关。对细胞在发育过程中使用基因和蛋白质的方式的基础研究提供了必要的工具，用于预测癌细胞如何使用相同的基因在特定组织内建立肿瘤并转移，将细胞释放到体内，侵入新的组织。最终，我们希望确定基因如何调节细胞在发育过程中发生粘附变化，并将这些发现应用于了解侵袭性癌症的晚期阶段。在实体瘤中，某些蛋白质可能会导致细胞相互粘附，而在转移的情况下，这些相同的蛋白质可能会从细胞中丢失，从而使细胞迁移离开初始肿瘤的部位。当癌细胞侵入新组织时，这些粘附蛋白可能会再次产生，并决定癌细胞可以粘附并形成肿瘤的组织类型。通过了解主要基因通路如何在发育背景下控制粘附，我们将更全面地了解这些基因如何在癌症建立和发展过程中控制细胞行为。

DESCRIPTION (provided by applicant): Somitogenesis is a dynamic process that integrates global and local signaling with cell morphogenesis to produce an ordered array of metameric units, or somites, along the axis of vertebrate embryos. The goal of this project is to understanding how the read out of Notch, Fgf, Wnt and Retinoic acid pathways is combined to influence cell behavior mediated by protocadherins during somite boundary formation. A Xenopus explant system will be developed to visualize the behavior of cells within anterior or posterior somite compartments under normal and experimental conditions. The role of a novel protocadherin, paraxial protocadherin 2 (PAPC2), in establishing changes in cell-cell interactions at somite boundaries will be examined using this explant system. Finally, the enhancer regions controlling PAPC2 expression at forming somite boundaries will be isolated to further understand how input of signaling in the presomitic mesoderm positions expression of genes that act at boundary formation. Changes in protocadherin expression as well as misregulation of Wnt, Fgf, Notch, and Retinoic acid signaling pathways are seen during cancerous tumor growth and metastasis. Understanding the way these pathways are integrated during development to change cell behavior will provide strong experimental evidence for creating informed models that will help to elucidate the role of these signaling pathways in the progression of disease. Many ofthe genes that cause growth and establishment of tumors are also involved in the early development of embryos. Basic research into the ways cells use genes and the proteins they produce during development provides necessary tools for predicting how cancerous cells are using the same genes to establish tumors within specific tissues and to metastasize, releasing cells into the body that will invade new tissues. Ultimately, we hope to determine how genes are regulating cells' that are undergoing changes in adhesion during development and apply these findings to understanding the advanced stages of invasive forms of cancer. In solid tumors, certain proteins may cause cells to stick to one another, while in cases of metastasis, these same proteins may be lost from cells, allowing cells to migrate away from the site ofthe initial tumor. When cancerous cells invade new tissues, these adhesion proteins may be produced again and determine what type of tissues cancer cells can adhere to and form tumors in. By understanding how major gene pathways control adhesion in a developmental context, we will more fully understand how these genes control cell behavior during cancer establishment and progression.