In vivo manipulation of heparan sulfate structure and its effect on Drosophila development
In vivo manipulation of heparan sulfate structure and its effect on Drosophila development
复制标题
DOI：
10.1093/glycob/cwq202
复制
发表时间：
2011-05-01
期刊：
影响因子：
4.3
通讯作者：
Nakato, Hiroshi
中科院分区：
文献类型：
--
作者：
Kamimura, Keisuke;Maeda, Nobuaki;Nakato, Hiroshi
硫酸乙酰肝素蛋白聚糖（HSPG）通过与许多配体蛋白相互作用参与广泛的生物过程。这些相互作用的性质在很大程度上取决于HSPG的硫酸乙酰肝素（HS）部分，其通过各种HS修饰酶（HSME）进行一系列修饰。虽然已经开始研究单个HSME中的改变对生理过程的影响，但仍然难以理解这些分子的组合如何控制HS的结构和功能。在这里，我们系统地操纵HS结构，并分析其对形态发生和信号传导的影响，使用遗传上易于处理的模式生物果蝇。我们产生了单独或组合过表达HSME的转基因果蝇品系。HS的不饱和二糖分析表明，各种HSME的表达产生不同的HS结构，和其他HSME的共表达的影响HSME的酶活性。此外，这些转基因HSME动物显示出不同程度的致死性，并且HSME的子集由于Wnt和骨形态发生蛋白信号传导的缺陷活性而引起特定的形态缺陷。HS不饱和二糖组成与HSME动物的发育缺陷之间没有明显的关系，这表明其他结构因素，如结构域组织或硫酸化序列，可能调节HS的功能。
Heparan sulfate proteoglycans (HSPGs) participate in a wide range of biological processes through interactions with a number of ligand proteins. The nature of these interactions largely depends on the heparan sulfate (HS) moiety of HSPGs, which undergoes a series of modifications by various HS-modifying enzymes (HSMEs). Although the effects of alterations in a single HSME on physiological processes have started to be studied, it remains elusive how a combination of these molecules control the structure and function of HS. Here we systematically manipulated the HS structures and analyzed their effect on morphogenesis and signaling, using the genetically tractable model organism, Drosophila. We generated transgenic fly strains overexpressing HSMEs alone or in combination. Unsaturated disaccharide analyses of HS showed that expression of various HSMEs generates distinct HS structures, and the enzymatic activities of HSMEs are influenced by coexpression of other HSMEs. Furthermore, these transgenic HSME animals showed a different extent of lethality, and a subset of HSMEs caused specific morphological defects due to defective activities of Wnt and bone morphogenetic protein signaling. There is no obvious relationship between HS unsaturated disaccharide composition and developmental defects in HSME animals, suggesting that other structural factors, such as domain organization or sulfation sequence, might regulate the function of HS.