Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, 55455, USA.
Glycobiology. 2011 May;21(5):607-18. doi: 10.1093/glycob/cwq202. Epub 2010 Dec 7.
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.
硫酸乙酰肝素蛋白聚糖（HSPGs）通过与许多配体蛋白的相互作用参与广泛的生物学过程。这些相互作用的性质在很大程度上取决于 HSPGs 的硫酸乙酰肝素（HS）部分，它会被各种 HS 修饰酶（HSMEs）进行一系列修饰。尽管已经开始研究单个 HSME 的改变对生理过程的影响，但这些分子如何组合来控制 HS 的结构和功能仍然难以捉摸。在这里，我们使用遗传上易于操作的模式生物果蝇，系统地操纵 HS 结构，并分析其对形态发生和信号转导的影响。我们生成了单独或组合过表达 HSMEs 的转基因果蝇品系。HS 的不饱和二糖分析表明，各种 HSME 的表达产生了不同的 HS 结构，并且 HSME 的酶活性受到其他 HSME 共表达的影响。此外，这些转基因 HSME 动物表现出不同程度的致死率，并且由于 Wnt 和骨形态发生蛋白信号转导的活性缺陷，一部分 HSMEs 导致特定的形态缺陷。HSME 动物中 HS 不饱和二糖组成与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。
