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 和含有糖胺多聚糖(GAG)的硫酸软骨素和/或 它们附着的蛋白质对调节生长很重要。 因子信号。然而，支持这一观点的活体证据 是很少的，部分原因是突变扰乱了 目前还没有GAG聚合物和核心蛋白可用。我们有 在果蝇中鉴定出超kasper基因(SkA)，并发现它 编码UDP-葡萄糖脱氢酶，这是生产所必需的 含有二糖的葡萄糖酸盐，它们反过来又是建筑物 肝素和硫酸软骨素堵塞。令人惊讶的是，突变 在这个一般的代谢基因中产生突变的表型，表明 无翼信号中的特定阻塞。在此之后，我们也有 发现果蝇syndecan基因的突变是 脊椎动物中的硫酸乙酰肝素，与基因突变相互作用 蓬头垢面，是无翼信号通路的关键组成部分。这些 观察表明，蛋白多糖和GAG对 体内生长因子信号传导。然而，他们提出了一些问题，比如 Syndecan在生长因子信号转导中的作用机制 特别是一般的和无翼的信号。我们建议探索 这些机制，并测试共同受体模型，共同聚集模型 和假定Syndecan/Wingless的扩散调节器模型 互动。这些问题可以通过测试效果来解决 体内利用发育和遗传修饰的转基因的研究 接近了。蛋白多糖参与WNT及可能的其他 生长因子信号通路为该机制增加了一个新的维度 细胞之间的信号传输。Syndecan和Superpenkasper都是 在哺乳动物中有高度保守的同源物，这意味着可能的保护 功能的一部分。此外，果蝇的无翼基因编码一种 哺乳动物肿瘤致癌基因Int-1的同源基因 蓬头垢面、毛茸茸的和螳螂的基因都高度保守。 无翼信令的下游组件，在功能上 可在脊椎动物和果蝇之间互换。因此，这些研究 将有助于我们理解管理增长因素的原则 一般的信号转导，特别是WG信号通路。 此外，这些体内研究可能有助于理解 人类中的一些畸形。

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.