Dissecting mechanisms underlying the Wnt/PCP signaling in endoderm morphogenesis

剖析内胚层形态发生中 Wnt/PCP 信号传导的机制

• 批准号: 2054512
• 负责人: Fang Lin
• 金额: $ 100万
• 依托单位: University of Iowa
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2054512&HistoricalAwards=false
• 关键词: Dissecting; mechanisms; underlying; Wnt; PCP

The digestive system is essential for animal function. During the development of the embryo, cells in the deepest tissue layer, which is known as the endoderm, move relative to one another to produce the gut and its associated organs. This movement is required for cell-to-cell communication via a set of proteins that comprise a signaling pathway, whose activity is also essential for many other events during development. The details of how this signaling controls the movement of endodermal cells are not clear, and such knowledge will be crucial to understanding how the gut is formed. The Lin laboratory has identified a subset of the genes in this signaling pathway critical for the above-described movements of the endodermal cells. This research group will apply its expertise in zebrafish genetics and in vivo imaging, as well as established tools, to determine how this signaling pathway controls the movement of endodermal cells during gut development. This study is expected to lead to a clear understanding of how endoderm movements are controlled, which will be broadly applicable to gut development in other animals (including humans). The PI is also passionate about training the next generation of research scientists. She will continue to use zebrafish as a platform for promoting science education at multiple levels, including providing training for postdoctoral fellows and graduate students, research experience for undergraduates, and engaging outreach activities for grade students. The endoderm contributes to the development of the gut and its associated organs. Signaling by the Wnt/planar cell polarity (PCP) pathway has been implicated in endoderm morphogenesis during gut development, but the underlying mechanisms are unclear. The objective of the proposed research is to determine how Wnt/PCP signaling controls endoderm convergence and extension (C&E)—an early step in gut formation, abnormalities in which lead to congenital defects in the digestive system. The Lin laboratory will use transgenic zebrafish lines in which the endoderm is labeled with fluorescent proteins and sensors to perform high-resolution in vivo imaging, in combination with genetic manipulations (global and tissue-specific) and cell biology tools. These will enable them to dissect the mechanisms whereby components of the Wnt/PCP signaling pathway, including its regulator, glypican 4 (Gpc4), orchestrate endodermal C&E. This study is expected to provide a clear understanding of the cellular and molecular mechanisms that control endodermal morphogenesis during gut development. In addition, the results are expected to be applicable to other species and to several other aspects of embryogenesis in which Wnt/PCP signaling is known to play critical roles.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

消化系统对于动物功能至关重要。在胚胎的发展过程中，最深的组织层中的细胞（被称为内胚层）相对移动以产生肠道及其相关组织。通过一组构成信号途径的蛋白质的细胞间通信需要这种运动，其活动对于开发过程中许多其他事件也是必不可少的。该信号如何控制内胚细胞运动的细节尚不清楚，并且这种知识对于理解肠道的形成至关重要。 LIN实验室已经确定了该信号传导途径中基因的子集，对于上胚层细胞的上述运动至关重要。该研究小组将在斑马鱼遗传学和体内成像以及已建立的工具中运用其专业知识，以确定该信号通路如何控制肠道发育过程中内胚层细胞的运动。预计这项研究将使人们对内胚层运动的控制方式有清晰的了解，这将广泛适用于其他动物（包括人类）的肠道发展。 PI还热衷于培训下一代研究科学家。她将继续使用斑马鱼作为促进多个层次的科学教育的平台，包括为博士后研究员和研究生提供培训，本科生的研究经验以及为年级学生提供宣传活动。内胚层有助于肠道及其相关器官的发展。 Wnt/Planar细胞极性（PCP）途径在肠道发育过程中已在内胚层形态发生中实现了信号，但尚不清楚基本机制。拟议的研究的目的是确定Wnt/PCP信号如何控制内胚层收敛和扩展（C＆E） - 肠道形成的早期步骤，异常，导致消化系统中先天性缺陷。 LIN实验室将使用转基因斑马鱼线，其中内胚层用荧光蛋白和传感器标记，在体内成像中执行高分辨率，并结合遗传操纵（全球和组织特异性）和细胞生物学工具。这些将使他们能够剖析Wnt/PCP信号通路的组件，包括其调节剂，Glycan 4（GPC4），编排内胚层C＆E。预计研究将对控制肠道发育过程中内胚层形态发生的细胞和分子机制有清晰的了解。此外，预计该结果将适用于其他物种，并且已知Wnt/PCP信号传导的其他几个方面都起着关键作用。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的审查标准来评估的。