Recognition of sulfated hexosamine upon construction of the nervous system

我们产生了N-乙酰葡糖胺6-磺基转移酶-1（GlcNAc6ST-1）缺陷的小鼠。与野生型小鼠相比，这些小鼠在淋巴细胞归巢至淋巴结中表现出较低的活性，从而确定GlcNAc6ST-1参与L-选择素配体的合成。国际合作产生了GlcNAc6ST-1和-2缺陷的双敲除小鼠。使用双敲除小鼠的研究揭示了GlcNAc与ST-1和ST-2在L-选择素配体的产生中协同作用。GlcNAc6ST-1也参与硫酸角质素的合成。在GlcNAc6ST-1敲除小鼠中，脑损伤后的胶质瘢痕形成减少，表明硫酸角质素通过促进胶质瘢痕形成来阻碍受损脑的修复。中期因子是一种肝素结合生长因子，可促进靶细胞的生长、存活和迁移。在中期因子和多效生长因子（生长因子家族的另一个成员）中双重缺陷的小鼠表现出听觉缺陷和雌性不育，并且自发运动活动减少。使用来自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。这些活性是中期因子促进神经发生的基础。明确了与中期因子强结合所需的糖胺聚糖结构是由硫酸软骨素E单元或硫酸乙酰肝素三硫酸化单元组成的重复结构。作为中期因子受体的蛋白聚糖、整合素和低密度脂蛋白受体相关蛋白是重要的，并被认为在中期因子存在下形成分子复合物。在少突胶质细胞胶质细胞样细胞的过程形成后，神经聚糖C，一种部分时间的蛋白聚糖也被鉴定为受体的组分。

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.