Regulation of Wingless(Wg) signaling and morphogen gradi

Wingless(Wg) 信号传导和形态发生素梯度的调节

基本信息

批准号：
7031776
负责人：
XINHUA LIN
金额：
$ 24.28万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2007-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7031776
关键词：
Drosophilidae biological signal transduction cell membrane enzyme activity gene interaction heparan sulfate imaginal disc immunoprecipitation invertebrate embryology molecular genetics mucopolysaccharides polymerase chain reaction protein biosynthesis protein localization protein structure function protein transport proteoglycan receptor binding

项目摘要

Drosophila Wingless (Wg) encodes a secreted protein of the Wnt family and acts both short-range inducer and long-range morphogen in many developmental processes. The extracellular Wg protein has been shown to activate its signaling cascade by binding to the seven-pass transmembrane receptors of the Frizzled (Fz) family. Although intracellular events trigged by Wg proteins have been extensively characterized in past several years, it is poorly understood how Wg protein travels from the cells of its synthesis to form morphogen gradient through a field of cells and how Wg protein forms active complex with its receptors to activate its signaling cascade. Recently, genetic analyses in Drosophila demonstrated that Wg signaling and Wg protein distributions are modulated by heparan sulfate proteoglycan (HSPG), a family of cell surface macromolecules that are composed of a protein core attached to Glycosaminoglycan (GAG) chains. Mutations in enzymes that generate or modify the GAG chains, exhibit phenotypes reminiscent of loss of Wingless (Wg) and lead to a loss of extracellular Wg proteins. Preliminary results also demonstrate that Drosophila glypican type of HSPGs are involved in Wg signaling. Our hypothesis is that HSPGs play specific roles in Wg ligand/receptor interactions as well as its distribution through field of cells. To gain insights into the function and specificity of HSPG in Wg signaling and morphogen gradient formation, we propose to further analyze the roles of both protein cores encoded by Drosophila Glypicans (Dly and Dally) and the specific enzymes involved in biosynthesis of the HS GAG chains. Altogether, our genetic and biochemical analyses of HSPGs will elucidate the role of HSPGs in regulating morphogen gradient formation and signaling of Wg proteins that play major roles in both developmental processes and oncogenesis.

果蝇 Wingless (Wg) 编码 Wnt 家族的分泌蛋白，并在许多发育过程中发挥短程诱导剂和长程形态发生素的作用。细胞外 Wg 蛋白已被证明可以通过与卷曲 (Fz) 家族的七次跨膜受体结合来激活其信号级联。尽管在过去几年中，Wg 蛋白触发的细胞内事件已被广泛表征，但人们对 Wg 蛋白如何从其合成的细胞移动以通过细胞区域形成形态发生素梯度以及 Wg 蛋白如何与其受体形成活性复合物以形成形态发生素梯度知之甚少。激活其信号级联。最近，果蝇的遗传分析表明，Wg 信号传导和 Wg 蛋白分布受到硫酸乙酰肝素蛋白聚糖 (HSPG) 的调节，HSPG 是细胞表面大分子家族，由附着于糖胺聚糖 (GAG) 链的蛋白核心组成。生成或修饰 GAG 链的酶突变会表现出类似 Wingless (Wg) 损失的表型，并导致细胞外 Wg 蛋白的损失。初步结果还表明，果蝇磷脂酰肌醇蛋白聚糖类型的 HSPG 参与 Wg 信号传导。我们的假设是 HSPG 在 Wg 配体/受体相互作用及其在细胞领域的分布中发挥特定作用。为了深入了解 HSPG 在 Wg 信号传导和形态发生素梯度形成中的功能和特异性，我们建议进一步分析果蝇 Glypicans 编码的蛋白质核心（Dly 和 Dally）以及参与 HS GAG 链生物合成的特定酶的作用。总而言之，我们对 HSPG 的遗传和生化分析将阐明 HSPG 在调节形态发生素梯度形成和 Wg 蛋白信号传导中的作用，Wg 蛋白在发育过程和肿瘤发生中发挥重要作用。