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（由申请人提供）：细胞外信号配体非常有效，可以在许多细胞类型中诱导反应。许多配体，例如保守的 Wnt 信号配体家族，在高浓度和低浓度下都有活性。由于它们的功能如此广泛，因此组织和器官控制这些信号蛋白的细胞外水平和扩散至关重要。在本提案中，我们研究了单一来源的 Wnt 蛋白如何在果蝇卵巢中发挥作用，向近端细胞和远端细胞发出不同的信号。我们的分析表明，这个 Wnt 池调节生殖系干细胞和卵泡干细胞，它们最终必须协调才能形成卵子。两种类型的 Wnt 信号传导均被一种新的分子模块改变，该模块由磷脂酰肌醇蛋白聚糖 Dally 样蛋白 (Dlp) 和基质金属蛋白酶 (Mmp2) 组成。在第一个目标中，我们分析了 Dlp/Mmp2 模块在调节近端和远端 Wnt 信号传导方面如何具有不同的功能。在第二个目标中，我们研究了 Mmp2 在细胞水平上如何改变 Dlp 运输。在第三个目标中，我们研究了一个小 一组 Wnt 分泌细胞通过“轮流”维持恒定的 Wnt 蛋白胞外水平来协调其生产。这项工作对于理解组织如何利用有效的细胞外信号来执行多项任务具有重要意义。