N-Acetylglucosamine 6-O-Sulfotransferase-1-Deficient Mice Show Better Functional Recovery after Spinal Cord Injury
N-Acetylglucosamine 6-O-Sulfotransferase-1-Deficient Mice Show Better Functional Recovery after Spinal Cord Injury
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DOI：
10.1523/jneurosci.2570-09.2010
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发表时间：
2010-04-28
影响因子：
5.3
通讯作者：
Kadomatsu, Kenji
中科院分区：
文献类型：
--
作者：
Ito, Zenya;Sakamoto, Kazuma;Kadomatsu, Kenji
成年中枢神经系统中的神经元在损伤后不能自发再生。脊髓损伤后可诱导产生硫酸糖胺聚糖，但其生物学意义尚不清楚。在这里，我们研究了硫酸角质素在脊髓损伤后功能恢复中的作用，使用在CNS中缺乏5D4反应性硫酸角质素的N-乙酰葡糖胺6-O-磺基转移酶-1缺陷的小鼠。我们在第10胸节造成了挫伤。在野生型小鼠中，损伤后诱导N-乙酰葡糖胺6-O-磺基转移酶-1和硫酸角质素的表达，但在缺陷型小鼠中不诱导。野生型和缺陷型小鼠表现出相似程度的硫酸软骨素诱导和CD 11b阳性炎性细胞募集。然而，运动功能的恢复，评估的脚步测试，足迹测试，和Basso小鼠量表运动评分，是显着更好的缺陷小鼠。此外，在枕颈区电刺激后，缺陷小鼠表现出病变下方神经肌肉系统功能的恢复。此外，在缺陷小鼠中，皮质脊髓束和中缝脊髓束的轴突再生得到促进。使用原代小脑颗粒神经元的体外试验表明，硫酸角质素蛋白多糖是蛋白多糖介导的抑制神经突生长所必需的。这些数据共同表明硫酸角质素表达与脊髓损伤后的功能障碍密切相关。N-乙酰葡糖胺6-O-磺基转移酶-1缺陷小鼠是研究硫酸角质素在CNS中作用的良好模型。
Neurons in the adult CNS do not spontaneously regenerate after injuries. The glycosaminoglycan keratan sulfate is induced after spinal cord injury, but its biological significance is not well understood. Here we investigated the role of keratan sulfate in functional recovery after spinal cord injury, using mice deficient in N-acetylglucosamine 6-O-sulfotransferase-1 that lack 5D4-reactive keratan sulfate in the CNS. We made contusion injuries at the 10th thoracic level. Expressions of N-acetylglucosamine 6-O-sulfotransferase-1 and keratan sulfate were induced after injury in wild-type mice, but not in the deficient mice. The wild-type and deficient mice showed similar degrees of chondroitin sulfate induction and of CD11b-positive inflammatory cell recruitment. However, motor function recovery, as assessed by the footfall test, footprint test, and Basso mouse scale locomotor scoring, was significantly better in the deficient mice. Moreover, the deficient mice showed a restoration of neuromuscular system function below the lesion after electrical stimulation at the occipito-cervical area. In addition, axonal regrowth of both the corticospinal and raphespinal tracts was promoted in the deficient mice. In vitro assays using primary cerebellar granule neurons demonstrated that keratan sulfate proteoglycans were required for the proteoglycan-mediated inhibition of neurite outgrowth. These data collectively indicate that keratan sulfate expression is closely associated with functional disturbance after spinal cord injury. N-acetylglucosamine 6-O-sulfotransferase-1-deficient mice are a good model to investigate the roles of keratan sulfate in the CNS.