Recognition of sulfated hexosamine upon construction of the nervous system

我们产生了N-乙酰氨基葡萄糖6-磺基转移酶-1(GlcNAc6ST-1)缺陷小鼠。与野生型小鼠相比，这些小鼠的淋巴细胞归巢到淋巴结的活性较低，证实GlcNAc6ST-1参与了L-选择素配体的合成。国际合作产生了同时缺乏GlcNAc6ST-1和-2的双基因敲除小鼠。使用双基因敲除小鼠的研究表明，GlcNAc和ST-1和-2在生产L-选择素配体方面是协同作用的。GlcNAc6ST-1还参与了硫酸角蛋白的合成。在GlcNAc6ST-1基因敲除小鼠中，脑损伤后胶质细胞瘢痕的形成减少，表明硫酸角蛋白通过促进胶质细胞瘢痕的形成阻碍了脑损伤的修复。中期因子是一种与肝素结合的生长因子，能促进靶细胞的生长、存活和迁移。同时缺乏中期因子和多营养素(生长因子家族的另一成员)的小鼠表现出听力障碍和雌性不孕，自发运动活动减少。利用中期因子缺陷小鼠的神经前体细胞，我们发现中期因子促进神经前体细胞的生长和存活，而不影响其分化能力。这些活动是中期因子促进神经发生的基础。与中期因子强结合所需的糖胺多糖结构被阐明为由硫酸软骨素E单位或硫酸乙酰肝素三硫酸单位组成的重复结构。作为中期因子受体的蛋白多糖、整合素和低密度脂蛋白受体相关蛋白具有重要作用，并被认为在中期因子存在的情况下形成分子复合体。在形成少突胶质前体细胞神经多糖C的过程中，一种兼职的蛋白多糖也被鉴定为该受体的一个组成部分。

We generated mice deficient in N-acetylglucosamine 6-sulfotransferase-1 (GlcNAc6ST-1). These mice exhibited lower activity in lymphocyte homing to lymph nodes compared to wild-type mice, establishing that GlcNAc6ST-1 is involved in synthesis of L-selectin ligand. International collaboration yielded double knockout mice deficient in both GlcNAc6ST-1 and -2. Studies using the double knockout mice revealed that GlcNAc&ST-1 and -2 co-operate in production of L-selectin ligand. GlcNAc6ST-1 was also involved in synthesis of keratan sulfate. Glia scar formation upon brain injury was reduced in GlcNAc6ST-1 knockout mice, indicating that keratan sulfate hinders repair of injured brain through promotion of glia scar formation. Midkine is a heparin-binding growth factor, which promotes growth, survival and migration of target cells. Mice doubly deficient in both midkine and pleiotrophin, another member of the growth factor family, exhibited auditory deficits and female infertility, and was reduced in spontaneous locomotive activity. Using neural precursor cells derived from midkine-deficient mice, we found that midkine promotes growth and survival of neural precursor cells without affecting their differentiation capability. These activities are the basis of promotion of neurogenesis by midkine. The glycosaminoglycan structure required for strong binding to midkine was clarified to be repeated structures composed of chondroitin sulfate E units or heparan sulfate trisulfated units. As midkine receptors, proteoglycans, integrins and low density lipoprotein receptor-related proteins are important, and were proposed to form molecular complex in the presence of midkine. Upon process formation of oligodendrocyte precursor-like cells, neuroglycan C, a part time proteoglycan was also identified as a component of the receptor.