Action mechanisms of galectin-1, CNTF and phosphacan for the regulation of axonal regeneration

• Project/Area Number: 17500267
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokyo Metropolitan Organization for Medical Research
• Principal Investigator: SANGO Kazunori Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience, Staff Scientist, 東京都神経科学総合研究所, 副参事研究員 (50291943)
• Co-Investigator(Kenkyū-buntansha): KAWANO Hitoshi Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience, Staff Scientist, 東京都神経科学総合研究所, 副参事研究員 (20161341) ; HORIE Hidenori Waseda University, Organization for General Research, Professor, 総合研究機構, 教授 (80046135)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: axonal regeneration / galectin-1 / ciliary neurotrophic factor / phosphacan / neuronal cell culture / dorsal root ganglion neurons / Schwann cells / signal transduction / 脊髄後根神経節細胞 / マクロファージ / 網膜

Research Abstract

We investigated the action mechanisms of growth-promoting molecules such as oxidized galectin-1 and ciliary neurotrophic factor (CNTF) and regulatory molecules such as chondroitin sulfate proteoglycans (especially phosphacan) in axonal regeneration after injury.
(1)Galectin-1 and CNTF : Immunohistochemistry on the sections of adult rat dorsal root ganglia (DRG) revealed that galectin-1 was abundantly expressed in small-diameter sensory neurons and Schwann cells while CNTF expression was restricted to Schwann cells. In contrast to the findings in vivo, we observed intense immunoreactivity for both galectin-1 and CNTF in DRG neurons after 3 hours, 2 days and 7 days in culture. At later stages of culture, the immunoreactivity was detected in regenerating neurites. These results suggest that both molecules are synthesized and transported to neurites in cultured DRG neurons. In spite of lacking signal leading sequences, galectin-1 is likely to be externalized from intact DRG neurons and Schw ann cells through the non-classical secretory pathway, whereas CNTF appears to be released from disrupted Schwann cells after peripheral nerve injury. Galectin-1 converted from the reduced form to the oxidized form in the extracellular space is likely to stimulate macrophages to secrete several factors (e.g. interleukin-6, bran derived neurotrophic factor), while CNTF directly acts on DRG neurons to activate signal transduction pathways (e.g. JAK-STAT3, MEK-MAPK, PI3K-Akt).
(2)Chondroitin sulfate proteoglycans : Phosphacan purified from embryonic (E20) or postnatal (P7, P20) rat brain impaired attachment and neurite outgrowth of cultured adult rat DRG neurons. These inhibitory effects were dependent on dose (10μg/ml>1μg/ml>>0.1μg/ml) and age of rats from which the molecule was purified (P20>P7>E20). Since the structure of chondroitin sulfate of these preparations are immunologically and compositionally different, these findings suggest that variation of chondroitin sulfate chains plays important roles in the regulatory actions of phosphacan.

Research Products

• [Journal Article] Regeneration of nigrostriatal dopaminergic axons by degradation of chondroitin sulfate is accompanied by elimination of the fibrotic scar and glia limitans in the lesion site (2007)
  • Author(s): Li, H-P., Homma, A., Sango, K., Kawamura, H., Raisman, G., Kawano H.
  • Journal Title: Journal of Neuroscience Research 85 Pages: 536-547
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression and histochemical localization of ciliary neurotrophic factor in cultured adult rat dorsal root ganglion neurons (2007)
  • Author(s): Sango, K., Yanagisawa, H., Takaku, S.
  • Journal Title: Histochemistry and Cell Biology (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regeneration of nigrostriatal dopaminergic axons by degradation of chondroitin sulfate is accompanied by elimination of the fibrotic scar and glia limitans in the lesion site. (2007)
  • Author(s): Li, H-P., Homma, A., Sango, K., Kawamura, H., Raisman, G., Kawano H.
  • Journal Title: Journal of Neuroscience Research 85 Pages: 536-547
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regeneration of nigrostriatal dopaminergic axons by degradation of chondroitin sulfate is accompanied by elimination of the fibrotic scar and glia limitans in the lesion site. (2007)
  • Author(s): Li, H-P, Homma, A., Sango, K., Kawamura, H., Raisman, G., Kawano H.
  • Journal Title: Journal of Neuroscience Research 85 Pages: 536-547
• [Journal Article] Cultured adult animal neurons and Schwann cells give us new insights into diabetic neuropathy (2006)
  • Author(s): Sango, K., Saito, H., Takano, M., Tokashiki, A., Inoue, S., Horie, H.
  • Journal Title: Current Diabetes Reviews 2 Pages: 169-183
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High glucose-induced activation of the polyol pathway and changes of gene expression profiles in immortalized adult mouse Schwann cells IMS32 (2006)
  • Author(s): Sango, K., Suzuki, T., Yanagisawa, H., Takaku, S., Hirooka, H., Tamura, M., Watabe, K.
  • Journal Title: Journal of Neurochemistry 98 Pages: 446-458
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 成熟動物ニューロン・シュワン細胞の培養法を用いた、糖尿病性神経障害の病態解明へのアプローチ (2006)
  • Author(s): 三五一憲, 斎藤春洋, 堀江秀典
  • Journal Title: 末梢神経 Peripheral Nerve 17 Pages: 15-22
  • NAID: 10019603878
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cultured adult animal neurons and Schwann cells give us new insights into diabetic neuropathy. (2006)
  • Author(s): Sango, K., Saito, H., Takano, M., Tokashiki, A., Inoue, S., Horie, H.
  • Journal Title: Current Diabetes Reviews 2 Pages: 169-183
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High glucose-induced activation of the polyol pathway and changes of gene expression profiles in immortalized adult mouse Schwann cells IMPS. (2006)
  • Author(s): Sango, K., Suzuki, T., Yanagisawa, H., Takaku, S., Hirooka, H., Tamura, M., Watabe, K.
  • Journal Title: Journal of Neurochemistry 98 Pages: 446-458
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An approach to the pathogenesis of diabetic neuropathy with cultured adult animal neurons and Schwann cells. (Japanese) (2006)
  • Author(s): Sango, K., Saito, H., Horie, H.
  • Journal Title: Peripheral Nerve (Massho Shinkei) 17 Pages: 15-22
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cultured adult animal neurons and Schwann cells give us new insights into diabetic neuronathy. (2006)
  • Author(s): Sango K, Saito H, Takano M, Tokashiki A, Inoue S, Horie H.
  • Journal Title: Current Diabetes Reviews 2 Pages: 169-183
• [Journal Article] High glucose-induced activation of the polyol pathway and changes of gene expression profiles in immortalized adult mouse Schwann cells IMS32. (2006)
  • Author(s): Sango K, Suzuki T, Yanagisawa H, Takaku S, Hirooka H, Tamura M, Watabe K.
  • Journal Title: Journal of Neurochemistry 98 Pages: 446-458
• [Journal Article] 成熟動物ニューロン・シュワン細胞の培養法を用いた、糖尿病性神経障害の病態解明へのアプローチ (2006)
  • Author(s): 三五一憲, 齋藤春洋, 堀江秀典
  • Journal Title: 末梢神経 Peripheral Nerve 17 Pages: 15-22
  • NAID: 10019603878
• [Journal Article] Inhibition of collagen synthesis overrides the age-related failure of regeneration of nigrostriatal dopaminergic axons (2005)
  • Author(s): Kawano, H., Li, H-P., Sango, K., Kawamura, K., Raisman, G.
  • Journal Title: Journal of Neuroscience Research 80 Pages: 191-202
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Oxidized galectin-1 is an essential factor for peripheral nerve regeneration (2005)
  • Author(s): Horie, H., Kadoya, T., Sango, K., Hasegawa, M.
  • Journal Title: Current Drug Targets 6 Pages: 385-394
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Impaired neurite outgrowth in the retina of a murine model of Sandhoff disease (2005)
  • Author(s): Sango, K., Takano, M., Ajiki, K., Tokashiki, A., Arai, N., Kawano, H., Horie, H., Yamanaka, S.
  • Journal Title: Investigative Ophththalmology and Visual Sciences 46 Pages: 3420-3425
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Establishment of immortalized Schwann cells from a Sandhoff mouse and corrective effect of recombinant human β- hexosaminidase A on the accumulated GM2 ganglioside (2005)
  • Author(s): Ohsawa, M., Kotani, M., Tajima, Y., Tsuji, D., Ishibashi, Y., Kuroki, A., Itoh, K., Watabe, K., Sango, K., Yamanaka, Y., Sakuraba, H.
  • Journal Title: Journal of Human Genetics 50 Pages: 460-457
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 糖尿病合併症治療薬 (2005)
  • Author(s): 三五一憲
  • Journal Title: 新薬展望2005(医薬ジャーナル増刊号) 41(S-1) Pages: 224-230
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 末梢神経系におけるガレクチン-1の発現分布と生理機能 (2005)
  • Author(s): 三五一憲, 堀江秀典, 門屋利彦
  • Journal Title: 末梢神経 Peripheral nerve 16 Pages: 1-8
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibition of collagen synthesis overrides the age-related failure of regeneration of nigrostriatal dopaminergic axons. (2005)
  • Author(s): Kawano, H., Li, H-P., Sango, K., Kawamura, K., Raisman, G.
  • Journal Title: Journal of Neuroscience Research 80 Pages: 191-202
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Oxidized galectin-1 is an essential factor for peripheral nerve regeneration. (2005)
  • Author(s): Horie, H., Kadoya, T., Sango, K., Hasegawa, M.
  • Journal Title: Current Drug Targets 6 Pages: 385-394
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Impaired neurite outgrowth in the retina of a murine model of Sandhoff disease. (2005)
  • Author(s): Sango, K., Takano, M., Ajiki, K., Tokashiki, A, Arai, N., Kawano, H., Horie, H., Yamanaka, S.
  • Journal Title: Investigative Ophththalmology and Visual Sciences 46 Pages: 3420-3425
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Establishment of immortalized Schwann cells from a Sandhoff mouse and corrective effect of recombinant human β-hexosaminidase A on the accumulated GM2 ganglioside. (2005)
  • Author(s): Ohsawa, M., Kotani, M., Tajima, Y., Tsuji, D., Ishibashi, Y., Kuroki, A., Itoh, K., Watabe K., Sango.K., Yamanaka, Y., Sakuraba, H.
  • Journal Title: Journal of Human Genetics 50 Pages: 460-457
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Medicines for diabetic complications.(Japanese) (2005)
  • Author(s): Sango, K.
  • Journal Title: Prospects of New Medicines (Shinyaku Tenbo) 41(S-1) Pages: 224-230
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Histochemical localization and possible functions of gelectin-1 in the peripheral nervous system. (Japanese) (2005)
  • Author(s): Sango, K., Horie, H., Kadoya, T.
  • Journal Title: Peripheral Nerve (Massho Shinkei) 16 Pages: 1-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Establishment of immortalized Schwann cells from a Sandhoff mouse and corrective effect of recombinant human β-hexosaminidase A on the accumulated GM2 ganglioside (2005)
  • Author(s): Ohsawa, M, Kotani, M., Tajima, Y., Tsuji, D., Ishibashi, Y., Kuroki, A., Itoh, K., Watabe, K., Sango, K., Yamanaka, Y., Sakuraba, H.
  • Journal Title: Journal of Human Genetics 50 Pages: 460-457
• [Journal Article] 末梢神経系におけるガレクチン-1の発現分布と生理機能 (2005)
  • Author(s): 三五一憲, 堀江秀典, 門屋利彦
  • Journal Title: 末梢神経Peripheral nerve 16 Pages: 1-8
• [Journal Article] Expression and histochemical localization of ciliary neurotrophic factor in cultured adult rat dorsal root ganglion neurons.
  • Author(s): Sango, K., Yanagisawa, H., Takaku, S.
  • Journal Title: Histochemistry and Cell Biology (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chondroitin sulfate proteoglycans in the peripheral nervous system after injury.
  • Author(s): Sango, K.
  • Journal Title: Neural Proteoglycans (Maeda, N., ed.)(Research Signpost Kerala, India) (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Neural Proteoglycans (2007)
  • Author(s): Sango, K., et al., (Maeda, N., Ed.)
  • Publisher: Research Signpost (Kerala, India)(印刷中)
  • Description: 「研究成果報告書概要(和文)」より