Regulation of Wingless(Wg) signaling and morphogen gradi

果蝇Wingless(Wg)编码Wnt家族的一种分泌型蛋白，在许多发育过程中既是短程诱导物，又是长程形成物。细胞外Wg蛋白已被证明通过与FrizzledFZ家族的七通道跨膜受体结合来激活其信号级联。尽管在过去的几年里，Wg蛋白触发的细胞内事件已经被广泛研究，但Wg蛋白如何从其合成的细胞中通过一系列细胞形成形态梯度，以及Wg蛋白如何与其受体形成活性复合体来激活其信号级联反应，还知之甚少。最近，对果蝇的遗传学研究表明，Wg信号和Wg蛋白分布受硫酸乙酰肝素蛋白多糖(HSPG)的调节。HSPG是一类细胞表面大分子，由连接在糖胺聚糖(GAG)链上的蛋白核心组成。产生或修改Gag链的酶的突变，表现出使人想起失去无翼(Wg)的表型，并导致细胞外Wg蛋白的丢失。初步结果还表明，果蝇Glypican型HSPGs参与了Wg信号转导。我们的假设是，HSPGs在Wg配体/受体的相互作用以及其在细胞场中的分布中发挥着特定的作用。为了深入了解HSPG在WG信号和形态梯度形成中的功能和特异性，我们建议进一步分析果蝇编码的蛋白质核心(Dly和Dally)以及参与HS GAG链生物合成的特定酶的作用。综上所述，我们对HSPGs的遗传和生化分析将阐明HSPGs在调节Wg蛋白的形态形成和信号转导中的作用，Wg蛋白在发育过程和肿瘤发生中发挥重要作用。

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.