Defects in glucuronate biosynthesis disrupt Wingless signaling in Drosophila.
Defects in glucuronate biosynthesis disrupt Wingless signaling in Drosophila.
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发表时间：
1997-08
期刊：
影响因子：
4.6
通讯作者：
T. Haerry;T. Heslip;J. Marsh;Michael B. O’Connor
中科院分区：
文献类型：
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作者：
T. Haerry;T. Heslip;J. Marsh;Michael B. O’Connor
体外实验表明，糖胺多聚糖(GAG)及其附着的蛋白质(蛋白多糖)对调节生长因子信号非常重要。然而，缺乏支持这一观点的体内证据，部分原因是尚未有破坏GAG聚合物和核心蛋白生产的突变。在这里，我们描述了果蝇超kasper(SkA)基因突变体的鉴定和特征。SkA基因编码UDP-葡萄糖脱氢酶，该酶产生葡萄糖醛酸，葡萄糖醛酸是合成肝素和硫酸软骨素的必要成分。SKA突变体未能将肝素侧链放在蛋白多糖上，如Syndecan。令人惊讶的是，这种一般代谢基因的胚系克隆产生的突变胚胎表现出与那些由无翼(Wg)信号通路基因功能丧失突变引起的胚胎角质层表型惊人的相似。SkA的合子丢失导致想象盘生长减少和图案缺陷，类似于WG突变体。此外，还观察到了SKA与WG和蓬乱突变体的遗传互作。这些数据证明了蛋白多糖和GAG在体内Wg信号转导中的重要性，并表明Wnt样生长因子可能对GAG生物合成的扰动特别敏感。
In vitro experiments suggest that glycosaminoglycans (GAGs) and the proteins to which they are attached (proteoglycans) are important for modulating growth factor signaling. However, in vivo evidence to support this view has been lacking, in part because mutations that disrupt the production of GAG polymers and the core proteins have not been available. Here we describe the identification and characterization of Drosophila mutants in the suppenkasper (ska) gene. The ska gene encodes UDP-glucose dehydrogenase which produces glucuronic acid, an essential component for the synthesis of heparan and chondroitin sulfate. ska mutants fail to put heparan side chains on proteoglycans such as Syndecan. Surprisingly, mutant embryos produced by germ-line clones of this general metabolic gene exhibit embryonic cuticle phenotypes strikingly similar to those that result from loss-of-function mutations in genes of the Wingless (Wg) signaling pathway. Zygotic loss of ska leads to reduced growth of imaginal discs and pattern defects similar to wg mutants. In addition, genetic interactions of ska with wg and dishevelled mutants are observed. These data demonstrate the importance of proteoglycans and GAGs in Wg signaling in vivo and suggest that Wnt-like growth factors may be particularly sensitive to perturbations of GAG biosynthesis.