IN VIVO ROLE OF PROTEOGLYCANS IN GROWTH FACTOR SIGNALING

生物学中的一个中心问题是如何在空间上调节旁分泌 组织中的信号。 体外实验表明，硫酸乙酰肝素 和含有糖胺聚糖（GAG）的硫酸软骨素和/或 它们所附着的蛋白质对于调节生长是重要的 因子信号。然而，支持这一观点的体内证据表明， 很少，部分原因是突变破坏了 尚未获得GAG聚合物和核心蛋白。 我们有 在果蝇中鉴定出suppenkasper基因（ska），发现它 编码UDP-葡萄糖脱氢酶，这是生产所必需的 含有双糖的葡萄糖酸盐， 乙酰肝素和硫酸软骨素糖胺聚糖块。 令人惊讶的是， 在这种一般情况下，代谢基因产生突变表型， 在无翼信号传递中的特定阻断。 在此之后，我们还 发现果蝇多配体蛋白聚糖基因的突变， 硫酸乙酰肝素在脊椎动物中， 这是无翅信号通路的关键组成部分。这些 观察表明，蛋白聚糖和GAG对于 体内生长因子信号传导。 然而，他们提出了一些问题， syndecan在生长因子信号传导中的作用机制 特别是无翼信号 我们建议探索 这些机制，并测试一个共同受体模型，一个共同聚类模型， 和假设Syndecan/Wingless的扩散调节器模型 互动 这些问题可以通过测试 在体内使用发育和遗传的修饰的转基因 接近。 蛋白聚糖参与Wnt和可能的其他蛋白质表达 生长因子信号通路增加了一个新的维度的机制 细胞之间的信号传输。 syndecan和suppenkasper 在哺乳动物中具有高度保守的同源物，这意味着可能的保护 的功能。 此外，果蝇的无翅基因编码一种 哺乳动物的肿瘤产生Int-1癌基因的同源物， disevelled，shaggy和armadillo基因都是高度保守的 无翼信号的下游组件， 脊椎动物和果蝇之间可以互换。 这些研究 将促进我们对生长因子管理原则的理解 信号传导，特别是WG信号传导途径。 此外，这些体内研究可能有助于理解 人类的一些畸形

A central problem in biology is how to spatially regulate paracrine signals in tissues. Experiments in vitro suggest that heparan sulfate and chondroitin sulfate containing glycosaminoglycans (GAGs) and/or the proteins to which they are attached are important for modulating growth factor signaling. However, in vivo evidence to support this view has been scanty, in part because mutations that disrupt the production of GAG polymers and the core proteins have not been available. We have identified the suppenkasper gene (ska) in Drosophila and found that it encodes UDP-glucose dehydrogenase which is essential for the production of gluconate containing disaccharides which, in turn, are the building blocks of heparan and chondroitin sulfate GAGs. Surprisingly, mutations in this general metabolic gene produce mutant phenotypes suggesting a specific block in wingless signaling. Following this, we have also found that mutations in the Drosophila syndecan gene, a major source of heparan sulfates in vertebrates, interact genetically with mutations of dishevelled, a key component of the wingless signaling pathway. These observations demonstrate that proteoglycans and GAGs are important for growth factor signaling in vivo. However, they raise questions about the mechanism of action of syndecan in growth factor signaling in general and wingless signaling in particular. We propose to explore those mechanisms and to test a coreceptor model, a co-clustering model and a diffusion regulator model of the postulated Syndecan/Wingless interaction. These questions can be addressed by testing the effects of modified transgenes in vivo using developmental and genetic approaches. The involvement of proteoglycans in Wnt and possibly other growth factor signaling pathways adds a new dimension to the mechanism of signal transmission between cells. Both syndecan and suppenkasper have highly conserved homologs in mammals implying possible conservation of function. In addition, the wingless gene of Drosophila encodes a homologue of the tumor producing Int-1 oncogene of mammals and the dishevelled, shaggy and armadillo genes are all highly conserved downstream components of wingless signaling and are functionally interchangeable between vertebrates and Drosophila. Thus these studies will foster our understanding of the principles governing growth factor signaling in general and the WG signaling pathway in particular. Further, these in vivo studies may help in understanding the basis of some dysmorphologies in humans.