Regulation of Wingless(Wg) signaling and morphogen gradi

果蝇无翅蛋白（Wg）编码Wnt家族的一种分泌蛋白，在许多发育过程中既是短距离诱导物又是长距离形态发生剂。 细胞外Wg蛋白已显示通过结合卷曲（Fz）家族的七次跨膜受体来激活其信号级联。 尽管Wg蛋白介导的细胞内事件在过去几年中得到了广泛的表征，但对Wg蛋白如何从其合成的细胞中穿过细胞场形成形态梯度以及Wg蛋白如何与其受体形成活性复合物以激活其信号级联反应知之甚少。 最近，在果蝇中的遗传分析表明，Wg信号和Wg蛋白分布的调节硫酸乙酰肝素蛋白聚糖（HSPG），一个家庭的细胞表面大分子，是由一个蛋白质核心连接到糖胺聚糖（GAG）链。 产生或修饰GAG链的酶中的突变表现出使人联想到无翼（Wg）缺失的表型，并导致细胞外Wg蛋白的缺失。初步结果还表明，果蝇glypican型的HSPGs参与Wg信号转导。 我们的假设是HSPG在Wg配体/受体相互作用及其在细胞中的分布中发挥特定作用。 为了深入了解HSPG在Wg信号传导和形态梯度形成中的功能和特异性，我们建议进一步分析果蝇Glypicans（Dly和Dally）编码的蛋白质核心和参与HS GAG链生物合成的特定酶的作用。 总之，我们的HSPGs的遗传和生化分析将阐明HSPGs在调节形态梯度形成和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起着重要作用。

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.