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.

消化系统对动物的功能至关重要。在胚胎发育过程中，被称为内胚层的最深组织层中的细胞相互移动，产生肠道及其相关器官。这种运动是细胞间通过一组蛋白质进行通信所必需的，这些蛋白质组成了信号通路，其活性对于发育过程中的许多其他事件也是必不可少的。这种信号如何控制内胚层细胞运动的细节尚不清楚，而这些知识对于理解肠道是如何形成的至关重要。Lin实验室已经确定了该信号通路中对上述内胚层细胞运动至关重要的基因子集。该研究小组将运用其在斑马鱼遗传学和体内成像方面的专业知识，以及已建立的工具，来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。这项研究有望使人们清楚地了解内胚层运动是如何被控制的，这将广泛适用于其他动物（包括人类）的肠道发育。PI还热衷于培养下一代研究科学家。她将继续利用斑马鱼作为一个平台，在多个层面上促进科学教育，包括为博士后和研究生提供培训，为本科生提供研究经验，并为年级学生开展外展活动。内胚层有助于肠道及其相关器官的发育。Wnt/平面细胞极性（PCP）信号通路与肠道发育过程中的内胚层形态发生有关，但其潜在机制尚不清楚。本研究的目的是确定Wnt/PCP信号如何控制内胚层收敛和延伸（C&amp；E），这是肠道形成的早期步骤，异常导致消化系统的先天性缺陷。林实验室将使用转基因斑马鱼系，其内皮被荧光蛋白和传感器标记，结合遗传操作（全局和组织特异性）和细胞生物学工具，进行高分辨率的体内成像。这将使他们能够剖析Wnt/PCP信号通路的组成部分，包括其调节剂glyypican 4 (Gpc4)，协调内胚层C&amp；E的机制。这项研究有望为肠道发育过程中控制内胚层形态发生的细胞和分子机制提供一个清晰的认识。此外，该结果有望适用于其他物种以及已知Wnt/PCP信号在胚胎发生中起关键作用的其他几个方面。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。