Regulation of Wingless(Wg) signaling and morphogen gradi

果蝇（Drosophila Wingless, 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剂又是远距离形态形成因子。胞外蛋白Wg已被证明通过与Frizzled （Fz）家族的七通跨膜受体结合来激活其信号级联。虽然在过去的几年里，Wg蛋白引发的细胞内事件已经被广泛地表征，但人们对Wg蛋白如何从其合成的细胞出发，在细胞范围内形成形态梯度，以及Wg蛋白如何与其受体形成活性复合物来激活其信号级联反应的了解甚少。最近，对果蝇的遗传分析表明，硫酸肝素蛋白多糖（HSPG）可调节Wg信号和Wg蛋白分布，HSPG是细胞表面大分子家族，由附着在糖胺聚糖（GAG）链上的蛋白核组成。产生或修饰GAG链的酶发生突变，表现出无翼（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，果蝇型HSPGs参与了Wg信号传导。我们的假设是HSPGs在Wg配体/受体相互作用及其在细胞场中的分布中起特定的作用。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编码的蛋白核（Dly和Dally）以及参与HS GAG链生物合成的特定酶的作用。总之，我们对HSPGs的遗传和生化分析将阐明HSPGs在调节Wg蛋白的形态梯度形成和信号传导中的作用，而Wg蛋白在发育过程和肿瘤发生中都起着重要作用。

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.