Mechanism of axon guidance after injury to the central nervous system.

• Project/Area Number: 15390438
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Chiba University
• Principal Investigator: YAMASHITA Toshihide Chiba University, Graduate School of Medicine, Professor, 大学院・医学研究院, 教授 (10301269)
• Project Period (FY): 2003 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥14,100,000 (Direct Cost: ¥14,100,000); Fiscal Year 2005: ¥4,100,000 (Direct Cost: ¥4,100,000); Fiscal Year 2004: ¥4,800,000 (Direct Cost: ¥4,800,000); Fiscal Year 2003: ¥5,200,000 (Direct Cost: ¥5,200,000)
• Keywords: regeneration / neuron / axon / glia / cell / protein

Research Abstract

To explore the mechanism of axon guidance of the injured neurons in the cetral nervous system (CNS), we screened the genes whose expression was changed after stimulation with neurotrophins using microarray technique. We got more than one hundred genes that showed enhanced expression. We focus on several genes that are expected to play a role in axon guidance, and decide to perform detailed analysis. We found that chimaerins are involved in desensitization of the neurons to some inhibitory molecules. The expression of chimaerins are enhanced in the cerebellar granule neurons after exposure to neurotrophins. When chimaerins are ectopically overexpressed, inhibition of neurite outgrowth by myelin-associated glycoprotein is reduced to the control level. In contrast, the effect of prior exposure to neurotrophins is abolished by the gene knockdown of chimaerins using siRNA. Thus, chimaerins may promote axon regeneration after injury to the CNS. In addition, we are interested in another gene, repulsive guidance molecule (RGM). RGMa inhibits mammalian CNS neurite outgrowth by a mechanism dependent on the activation of the Rho/Rho-kinase pathway. RGMa expression is observed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord, and is induced around the injury site following spinal cord injury. We developed an antibody to RGMa that efficiently blocks the effect of RGMa in vitro. Intrathecal administration of the antibody to rats with thoracic spinal cord hemisection results in significant axonal growth of the corticospinal tract, and improves functional recovery. Thus, RGMa plays an important role in limiting axonal regeneration after CNS injury, and the RGMa antibody offers a possible therapeutic agent in clinical conditions characterized by a failure of CNS regeneration.

Research Products

• [Journal Article] Wallerian degeneration involves Rho/Rho-kinase signaling. (2005)
  • Author(s): 山岸覚
  • Journal Title: Journal of Biological Chemistry 280 Pages: 20384-20388
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Binding of soluble myelin-associated glycoprotein to specific gangliosides induces the association of p75^NTR to lipid rafts and signal transduction. (2005)
  • Author(s): 藤谷昌司
  • Journal Title: Journal of Neurochemistry 94 Pages: 15-21
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Biological activity of neruotrophins is dependent on recruitment of Racl to lipid rafts. (2005)
  • Author(s): 藤谷昌司
  • Journal Title: Biochem. Biophys. Res. Commun. 327 Pages: 150-154
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] c-Jun N-terminal kinase activation in dorsal root ganglion contributes to pain hypersensivity. (2005)
  • Author(s): 銅冶英雄
  • Journal Title: Biochem. Biophys. Res. Commun. 335 Pages: 132-138
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ERK MAP kinase activation in dorsal root ganglion (DRG) and the spinal cord following DRG injury in rats. (2005)
  • Author(s): 銅冶英雄
  • Journal Title: Spine 30 Pages: 2252-2256
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Wallerian degeneration involves Rho/Rho-kinase signaling. (2005)
  • Author(s): Yamagishi, S., Fujitani, M., Hata, K., Kitajo, K., Mimura, F., Abe, H., Yamashita, T.
  • Journal Title: J.Biol.Chem. 280 Pages: 20384-20388
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Binding of soluble myelin associated glycoprotein to specific gangliosides induces the association of p75NTR to lipid rafts and signal transduction. (2005)
  • Author(s): Fujitani, M., Kawai, H., Proia, R.L., Kashiwagi, A., Yasuda, H., Yamashita, T.
  • Journal Title: J.Neurochem. 94 Pages: 15-21
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Biological activity of neurotrophins is dependent on recruitment of Rac1 to lipid rafts. (2005)
  • Author(s): Fujitani, M., Honda, A., Hata, K., Yamagishi, S., Tohyama, M., Yamashita, T.
  • Journal Title: Biochem.Biophys.Res.Commun. 327 Pages: 150-154
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] c-Jun N-terminal kinase activation in dorsal root ganglion contributes to pain hypresensitivity. (2005)
  • Author(s): Doya, H., Ohtori, S., Fujitani, M., Saito, T., Hata, K., Ino, H., Takahashi, K., Moriya, H., Yamashita, T.
  • Journal Title: Biochem.Biophys.Res.Commun. 335 Pages: 132-138
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] ERK MAP kinase activation in the dorsal root ganglion (DRG) and the spinal cord following DRG injury in rats. (2005)
  • Author(s): Doya, H., Ohtori, S., Takahashi, Ka., Aoki, Y., Ino, H., Takahashi, Y., Moriya, H., Yamashita, T.
  • Journal Title: Spine 30 Pages: 2252-2256
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Binding of soluble myelin-associated glycoprotein to specific gangliosides induces the association of p75^<NTR> to lipid rafts and signal transduction. (2005)
  • Author(s): 藤谷昌司
  • Journal Title: Journal of Neurochemistry 94 Pages: 15-21
• [Journal Article] Biological activity of neurotrophins is dependent on recruitment of Rac1 to lipid rafts. (2005)
  • Author(s): 藤谷昌司
  • Journal Title: Biochem.Biophys.Res.Commun. 327 Pages: 150-154
• [Journal Article] c-Jun N-terminal kinase activation in dorsal root ganglion contributes to pain hypersensitivity. (2005)
  • Author(s): 銅冶英雄
  • Journal Title: Biochem.Biophys.Res.Commun. 335 Pages: 132-138
• [Journal Article] ERK MAP kinase activation in the dorsal root ganglion (DRG) and the spinal cord following DRG injury in rats. (2005)
  • Author(s): 銅冶英雄
  • Journal Title: Spine 30 Pages: 2252-2256
• [Journal Article] Promotion of axon regeneration by MAG and Nogo through divergent signals downstream of G/G (2004)
  • Author(s): 長谷川結子
  • Journal Title: Journal of Neuroscience 24・30 Pages: 6826-6832
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Activation of Rho in the injured axons following spinal cord injury. (2004)
  • Author(s): Tomas Madura
  • Journal Title: EMBO Reports 5・4 Pages: 412-417
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] EphA receptors direct the differentiation of mammalian neural precursor cells through Ras/MAPK nathway (2004)
  • Author(s): 青木美和
  • Journal Title: Journal of Biological Chemistry 279・31 Pages: 32643-32650
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] P311 accelerates nerve regeneration of the axotomized facial nerve. (2004)
  • Author(s): 藤谷昌司
  • Journal Title: Journal of Neurochemistry 91・3 Pages: 737-744
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Chimaerins act downstream from neurotrophins in overcoming inhibition of neurite outgrowth by MAG. (2004)
  • Author(s): 水野龍吉
  • Journal Title: Journal of Neurochemistry 91・2 Pages: 395-403
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cytoplasmic p21^Cip/WAF1 enhances axonal regeneration and functional recovery after spinal cord injury in rats. (2004)
  • Author(s): 田中裕之
  • Journal Title: Neuroscience 127・1 Pages: 155-164
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Promotion of axon regeneration by MAG and Nogo through divergent signals downstream of G_i/G. (2004)
  • Author(s): Hasegawa, Y., Fujitani, M., Hata, K., Tohyama, M., Yamagishi, S., Yamashita, T.
  • Journal Title: J.Neurosci. 24-30 Pages: 6826-6832
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Activation of Rho in the injured axons following spinal cord injury. (2004)
  • Author(s): Madura, T., Yamashita, T., Kubo, T., Fujitani, M., Hosokawa, K., Tohyama, M.
  • Journal Title: EMBO Reports 5-4 Pages: 412-417
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] EphA receptors direct the differentiation of mammalian neural precursor cells through Ras/MAPK pathway. (2004)
  • Author(s): Aoki, M., Yamashita, T., Tohyama, M.
  • Journal Title: J.Biol.Chem. 279-31 Pages: 32643-32650
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] P311 accelerates nerve regeneration of the axotomized facial nerve. (2004)
  • Author(s): Fujitani, M., Yamagishi, S., Che, Y.-H., Hata, K., Kubo, T., Ino, H., Tohyama, M., Yamashita.T.
  • Journal Title: J.Neurochem. 91-3 Pages: 737-744
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chimaerins act downstream from neurotrophins in overcoming inhibition of neurite outgrowth by MAG. (2004)
  • Author(s): Mizuno, T., Yamashita, T., Tohyama, M.
  • Journal Title: J.Neurochem. 91-2 Pages: 395-403
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cytoplasmic p21^<Cip1/WAF1> enhances axonal regeneration and functional recovery after spinal cord injury in rats. (2004)
  • Author(s): Tanaka, H., Yamashita, T., Yachi, K, Fujiwara, K., Yoshikawa, K., Tohyama, M.
  • Journal Title: Neuroscience 127-1 Pages: 155-164
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] EphA receptors direct the differentiation of mammalian neural precursor cells through RAS/MAPK pathway. (2004)
  • Author(s): 青木美和
  • Journal Title: Journal of Biological Chemistry 279・31 Pages: 32643-32650
• [Journal Article] Cytoplasmic P21^<Cip1/WAF1> enhances axonal regeneration and functional recovery after spinal cord injury in rats. (2004)
  • Author(s): 田中裕之
  • Journal Title: Neuroscience 127・1 Pages: 155-164
• [Journal Article] RGMa inhibition promotes axonal growth and recovery after spinal cord injury.
  • Author(s): 羽田克彦
  • Journal Title: Journal of Cell Biol. 印刷中
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Delayed treatment with Rho-kinase inhibitor does not enhance axonal regeneration for functional recovery after spinal cord injury in rats.
  • Author(s): 西尾豊
  • Journal Title: Exp. Neurol. 印刷中
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Rho-kinase inhibitor enhance axonal regeneration and functional recovery after peripheral nerve injury.
  • Author(s): 平賀晃之
  • Journal Title: J. Peripher. Nerv. Syst. 印刷中
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adenoviral Gene Transfer in the Peripheral Nervous System.
  • Author(s): 渡辺(齊藤)朋子
  • Journal Title: J. Orthopaedic Sci.
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] RGMa inhibition promotes axonal growth and recovery after spinal cord injury.
  • Author(s): Hata, K., Fujitani, M., Yasuda, Y., Doya, H., Saito, T., Yamagishi, S., Mueller, B.K., Yamashita.T.
  • Journal Title: J.Cell Biol. (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Delayed treatment with Rho-kinase inhibitor does not enhance axonal regeneration or functional recovery after spinal cord injury in rats.
  • Author(s): Nishio, Y., Koda, M., Kitajo, K, Seto, M., Hata, K., Taniguchi, J., Moriya, H., Fujitani, M., Kubo, T., Yamashita, T.
  • Journal Title: Exp.Neurol. (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rho-kinase inhibition enhances axonal regeneration and functional recovery after peripheral nerve injury.
  • Author(s): Hiraga, A., Kuwabara, S., Douya, BL, Kanai, K., Fujitani, M., Taniguchi, J., Arai, K., Mori, M., Hattori, T., Yamashita, T.
  • Journal Title: J.Peripher.Nerv.Syst. (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adenoviral Gene Transfer in the Peripheral Nervous System.
  • Author(s): Saito-Watanabe, T., Ohtori, S., Koda, M., Aoki, Y., Doya, H., Shirasawa, H., Yamazaki, M., Moriya, H., Takahashi, K., Yamashita, T.
  • Journal Title: J.Orthopaedic Sci. (In press)
  • NAID: 10017328880
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adenoviral Gene Transfer in the Peripheral Nervous System.
  • Author(s): 渡辺(齋藤)朋子
  • Journal Title: J.Orthopaedic Sci. (印刷中)