N-acetylglucosamine 6-O-sulfotransferase-1-deficient mice show better functional recovery after spinal cord injury

• Published in: The Journal of neuroscience 2010-04, Vol.30 (17), p.5937-5947
• Main Authors: Ito, Zenya, Sakamoto, Kazuma, Imagama, Shiro, Matsuyama, Yukihiro, Zhang, Haoqian, Hirano, Kenichi, Ando, Kei, Yamashita, Toshihide, Ishiguro, Naoki, Kadomatsu, Kenji
• Format: Article
• Language: English
• Subjects: Animals; Axons - enzymology; Axons - physiology; Brain - physiopathology; Carbohydrate Sulfotransferases; CD11b Antigen - metabolism; Cells, Cultured; Chondroitin Sulfates - metabolism; Female; Keratan Sulfate - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity - physiology; Nerve Regeneration - physiology; Neural Pathways - enzymology; Neural Pathways - immunology; Neural Pathways - physiopathology; Neurites - enzymology; Neurites - physiology; Neuromuscular Junction - enzymology; Neuromuscular Junction - physiopathology; Rats; Rats, Sprague-Dawley; Recovery of Function - physiology; Spinal Cord Injuries - enzymology; Spinal Cord Injuries - immunology; Spinal Cord Injuries - physiopathology; Sulfotransferases - deficiency; Sulfotransferases - genetics; Sulfotransferases - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2570-09.2010

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.