N-acetylglucosamine 6-0-sulfotransferase-1 is required for brain keratan sulfate biosynthesis and glial scar formation after brain injury
N-acetylglucosamine 6-0-sulfotransferase-1 is required for brain keratan sulfate biosynthesis and glial scar formation after brain injury
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DOI：
10.1093/glycob/cwj115
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发表时间：
2006-08-01
期刊：
影响因子：
4.3
通讯作者：
Kadomatsu, Kenji
中科院分区：
文献类型：
--
作者：
Zhang, Haoqian;Muramatsu, Takashi;Kadomatsu, Kenji
硫酸角质素（KS）是一种糖胺聚糖，由在半乳糖和N-乙酰葡糖胺（GicNAc）的C6位具有硫酸酯残基的重复二糖单元组成。在中枢神经系统中参与KS合成的N-乙酰葡糖胺6-O-磺基转移酶（GlcNAc 6ST）一直未被鉴定。在这里，我们报告说，缺乏GlcNAc 6ST-1导致的损失5D4反应性脑KS和减少胶质瘢痕形成后，皮质刺伤小鼠。在GlcNAc 6ST-1缺陷小鼠的发育过程中，用KS特异性抗体5D4几乎检测不到脑中的KS表达。5D4抗体与蛋白酪氨酸磷酸酶（PTP），KS蛋白聚糖（KSPG）的反应性在缺陷小鼠中被消除。在成年人中，脑损伤诱导5D4反应性KS合成在野生型（WT）小鼠的受伤区域，但在缺陷小鼠。胶质瘢痕是通过反应性星形胶质细胞的积累形成的，并且是受损神经元轴突再生的主要障碍。反应性星形胶质细胞在两种基因型中出现的程度相似，但它们在缺陷小鼠的受伤区域中积累的程度较低。因此，缺陷小鼠在脑损伤后表现出明显的疤痕减少和增强的神经元再生。这些发现强调了GlcNAc 6ST-1在脑损伤后脑KS生物合成和胶质瘢痕形成中不可或缺的作用。
Keratan sulfate (KS) is a glycosaminoglycan composed of repeating disaccharide units with sulfate residues at the C6 positions of galactose and N-acetylglucosamine (GicNAc). The N-acetylglucosamine 6-O-sulfotransferase(s) (GlcNAc6ST) involved in the synthesis of KS in the central nervous system (CNS) has long been unidentified. Here, we report that a deficiency of GIcNAc6ST-1 leads to loss of 5D4-reactive brain KS and reduction of glial scar formation after cortical stab injury in mice. During the development of mice deficient in GIcNAc6ST-1, KS expression in the brain was barely detectable with the KS-specific antibody 5D4. The reactivity of 5D4 antibody with protein tyrosine phosphatase (PTP), a KS proteoglycan (KSPG), was abolished in the deficient mice. In adults, brain injury induced 5D4-reactive KS synthesis in the wounded area in wild-type (WT) mice but not in the deficient mice. Glial scar is formed via the accumulation of reactive astrocytes and is a major obstacle to axonal regeneration by injured neurons. Reactive astrocytes appeared to similar extents in the two genotypes, but they accumulated in the wounded area to a lesser extant in the deficient mice. Consequently, the deficient mice exhibited a marked reduction of scarring and enhanced neuronal regeneration after brain injury. These findings highlight the indispensable role of GIcNAc6ST-1 in brain KS biosynthesis and glial scar formation after brain injury.