Bridging Dynamic Signaling and Somite Morphogenesis

描述(申请人提供)：体细胞发生是一个动态过程，它将全局和局部信号与细胞形态发生相结合，沿着脊椎动物胚胎的轴线产生有序的异构体单位或体节。该项目的目标是了解Notch、Fgf、Wnt和维甲酸途径的读出如何结合在一起，在体节边界形成过程中影响由原钙粘附素介导的细胞行为。将开发一种非洲爪哇外植体系统，以可视化正常和实验条件下体节前部或后部细胞的行为。一种新的原钙粘附素，旁轴原钙粘附素2(PAPC2)，在建立体节边界细胞-细胞相互作用的变化中的作用将使用该外植体系统来检验。最后，将分离在形成体节边界处控制PAPC2表达的增强子区域，以进一步了解在卵裂期前中胚层中信号的输入如何定位在边界形成中起作用的基因的表达。在肿瘤的生长和转移过程中，可观察到原钙粘附素表达的变化以及WNT、成纤维细胞生长因子、Notch和维甲酸信号通路的错误调节。了解这些信号通路在发育过程中整合以改变细胞行为的方式，将为创建有助于阐明这些信号通路在疾病进展中的作用的知情模型提供强有力的实验证据。许多导致肿瘤生长和建立的基因也与胚胎的早期发育有关。对细胞如何使用基因及其在发育过程中产生的蛋白质的基础研究，为预测癌细胞如何利用相同的基因在特定组织内建立肿瘤和转移、释放将入侵新组织的细胞进入体内提供了必要的工具。最终，我们希望确定基因是如何调控细胞的，这些细胞在发育过程中经历粘附性的变化，并将这些发现应用于了解晚期侵袭性癌症。在实体肿瘤中，某些蛋白质可能会导致细胞彼此粘连，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，使细胞从最初的肿瘤位置迁移出去。当癌细胞侵入新的组织时，这些黏附蛋白可能会再次产生，并决定癌细胞可以附着在什么类型的组织中并在其中形成肿瘤。通过了解主要基因通路如何在发育过程中控制黏附，我们将更全面地了解这些基因如何控制癌症建立和发展过程中的细胞行为。

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.