Chondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury

Kosei Takeuchi, Nozomu Yoshioka, Susumu Higa Onaga, Yumi Watanabe, Shinji Miyata, Yoshino Wada, Chika Kudo, Masayasu Okada, Kentaro Ohko, Kanako Oda, Toshiya Sato, Minesuke Yokoyama, Natsuki Matsushita, Masaya Nakamura, Hideyuki Okano, Kenji Sakimura, Hitoshi Kawano, Hiroshi Kitagawa and Michihiro Igarashi ()
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Kosei Takeuchi: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Nozomu Yoshioka: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Susumu Higa Onaga: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Yumi Watanabe: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Shinji Miyata: Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Kobe 658 8558, Japan
Yoshino Wada: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Chika Kudo: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Masayasu Okada: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Kentaro Ohko: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Kanako Oda: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Toshiya Sato: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Minesuke Yokoyama: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Natsuki Matsushita: Translational Research Center (TRC), Ehime University Hospital, Shitsukawa
Masaya Nakamura: Keio University School of Medicine, 35 Shinanomachi, Tokyo 160 8582, Japan
Hideyuki Okano: Keio University School of Medicine, 35 Shinanomachi, Tokyo 160 8582, Japan
Kenji Sakimura: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan
Hitoshi Kawano: Laboratory of Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Tokyo 156 8506, Japan
Hiroshi Kitagawa: Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Kobe 658 8558, Japan
Michihiro Igarashi: Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata 951 8510, Japan

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: Abstract Extracellular factors that inhibit axon growth and intrinsic factors that promote it affect neural regeneration. Therapies targeting any single gene have not yet simultaneously optimized both types of factors. Chondroitin sulphate (CS), a glycosaminoglycan, is the most abundant extracellular inhibitor of axon growth. Here we show that mice carrying a gene knockout for CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme in CS biosynthesis, recover more completely from spinal cord injury than wild-type mice and even chondroitinase ABC-treated mice. Notably, synthesis of heparan sulphate (HS), a glycosaminoglycan promoting axonal growth, is also upregulated in TI knockout mice because HS-synthesis enzymes are induced in the mutant neurons. Moreover, chondroitinase ABC treatment never induces HS upregulation. Taken together, our results indicate that regulation of a single gene, T1, mediates excellent recovery from spinal cord injury by optimizing counteracting effectors of axon regeneration—an extracellular inhibitor of CS and intrinsic promoters, namely, HS-synthesis enzymes.

Date: 2013
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DOI: 10.1038/ncomms3740

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