Wnt/Wg Extracellular Ligand Distribution and Regulation

Wnt/Wg 细胞外配体分布和调节

• 批准号: 9054616
• 负责人: Andrea W Page-McCaw
• 金额: $ 32.19万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054616
• 关键词: Behavior Control; Biological Models; Cell Culture Techniques; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell membrane; Cell physiology; Cells; Cleaved cell; Complex; Data; Development; Diffuse; Diffusion; Distal; Drosophila genus; Endocytosis; Environment; Event; Family; Frequencies; Genes; Genetic; Glypican; Homeostasis; Ligands; Maintenance; Matrix Metalloproteinases; Mediating; Modeling; Molecular; Organ; Ovary; Paper; Pathway interactions; Peptide Hydrolases; Population; Process; Production; Protein Inhibition; Proteins; Proteolysis; Regulation; Signal Transduction; Signaling Molecule; Signaling Protein; Site; Source; Stem cells; Tissues; Wnt proteins; Work; animal tissue; cell behavior; cell type; egg; extracellular; germline stem cells; mutant; notch protein; novel; protein transport; public health relevance; receptor; response; stem cell niche; trafficking; tumor

 DESCRIPTION (provided by applicant): Extracellular signaling ligands are highly potent and can induce responses in many cell types. Many ligands, such as the conserved Wnt family of signaling ligands, are active at both high and low concentrations. Because they can function so broadly, it is essential that tissues and organs control the extracellular levels and diffusion of these signaling proteins. In this proposal, we investigate how a Wnt protein emanating from a single source functions in in the Drosophila ovary to signal differentially to proximal cells and distal cells. Our analysis shows that this Wnt pool regulates both the germline and follicle stem cells, which must ultimately coordinate to build an egg. Both types of Wnt signaling are altered by a new molecular module, composed of the glypican Dally-like protein (Dlp) and a matrix metalloproteinase (Mmp2). In the first Aim, we analyze how the Dlp/Mmp2 module has different functions in regulating proximal and distal Wnt signaling. In the second Aim we investigate how Dlp trafficking is altered by Mmp2 at a cellular level. In the third Aim we investigate how a small group of Wnt-secreting cells coordinate their production by "taking turns" maintaining constant extracellular levels of Wnt protein. This work is significant in understanding how tissues harness potent extracellular signals to perform multiple tasks.

 描述(申请人提供)：细胞外信号配体是高度有效的，可以在许多类型的细胞中诱导反应。许多配体，如保守的信号配体Wnt家族，在高浓度和低浓度下都是活性的。因为它们的功能如此广泛，所以组织和器官控制这些信号蛋白的细胞外水平和扩散是至关重要的。在这个方案中，我们研究了来自单一来源的Wnt蛋白如何在果蝇卵巢中发挥作用，以区别于近端细胞和远端细胞。我们的分析表明，这个Wnt池同时调节生殖系和卵泡干细胞，这两个干细胞最终必须协调才能形成卵子。这两种类型的Wnt信号都被一个新的分子模块改变，该模块由Glypcan Dally-like蛋白(DLP)和基质金属蛋白酶(MMP2)组成。在第一个目的中，我们分析了DLP/MMP2模块在调节近端和远端Wnt信号中的不同功能。在第二个目标中，我们调查MMP2是如何在细胞水平上改变DLP交易的。在第三个目标中，我们调查一个小的 一组分泌Wnt的细胞通过“轮流”维持细胞外恒定的Wnt蛋白水平来协调它们的生产。这项工作对于理解组织如何利用强大的细胞外信号来执行多项任务具有重要意义。