Studies on diversity of axon guidance mechanisms

• Project Area: Neural Diversity and Neocortical Organization
• Project/Area Number: 22123006
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: University of Tsukuba
• Principal Investigator: MASU Masayuki 筑波大学, 医学医療系, 教授 (20243032)
• Co-Investigator(Kenkyū-buntansha): SHIOMI Kensuke 筑波大学, 医学医療系, 講師 (00311598) ; MASU Kazuko 筑波大学, 医学医療系, 講師 (50344883)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥104,780,000 (Direct Cost: ¥80,600,000、Indirect Cost: ¥24,180,000); Fiscal Year 2014: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2013: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000); Fiscal Year 2012: ¥22,490,000 (Direct Cost: ¥17,300,000、Indirect Cost: ¥5,190,000); Fiscal Year 2011: ¥26,390,000 (Direct Cost: ¥20,300,000、Indirect Cost: ¥6,090,000); Fiscal Year 2010: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
• Keywords: 脳 / 発生 / 糖鎖 / 神経回路 / 大脳皮質 / ヘパラン硫酸 / 軸索ガイダンス / 皮質脊髄路 / 神経軸索 / スルファターゼ / 脳・神経 / 遺伝子 / 発生・分化

Outline of Final Research Achievements

We studied the roles of heparan sulfate in corticospinal tract formation. We generated the double knockout (DKO) mice for Sulf1 and Sulf2, which are normally required for 6-O-desulfation of heparan sulfate. We found that Sulf1/2 DKO mice had axon guidance defects in the corticospinal tract. The cortical axons abnormally projected towards the superior and inferior colliculi, and midline crossing did not occur normally in the pyramidal decussation. These results suggest that heparan sulfate modification by Sulf1/2 is required for normal corticospinal tract formation.

Research Products

• [Journal Article] Expression of the heparan sulfate 6-0-endosulfatases, Sulfl and Sulf2, in the avian and mammalian inner earsuggests a role for sulfation during inner ear development. (2015)
  • Author(s): Freeman SD, Keino-Masu K, Masu M, Ladher RK.
  • Journal Title: Dev Dyn Volume: 244 Pages: 168-180
  • DOI: 10.1002/dvdy.24223
  • Peer Reviewed / Open Access
• [Journal Article] ErbB2 dephosphorylation and anti-proliferative effects of neuregulin-1 in ErbB2-overexpressing cell lines; re-evaluation of their low-affinity interaction. (2013)
  • Author(s): Wang, R., Iwakura, Y., Araki, K., Keino-Masu, K., Masu, M., Wang, X., Takei, N., Higashiyama, S. and Nawa, H.
  • Journal Title: Scientific Reports Volume: 3 Pages: 1402-1402
  • DOI: 10.1038/srep01402
  • Peer Reviewed
• [Journal Article] A unique mouse model for investigating the properties of amyotrophic lateral sclerosis-associated protein TDP-43, by in utero electroporation. (2013)
  • Author(s): Akamatsu, M., Takuma, H., Yamashita, T., Okada, T., Keino-Masu, K., Ishii, K., Kwak, S., Masu, M., and Tamaoka, A.
  • Journal Title: Neurosci Res. Volume: 77 Pages: 234-241
  • DOI: 10.1016/j.neures.2013.09.009
  • NAID: 120007130577
  • Peer Reviewed
• [Journal Article] ヘパラン硫酸微細構造の組織特異性とその決定機 (2013)
  • Author(s): 桝和子、桝正幸
  • Journal Title: 医学のあゆみ Volume: 245 (7) Pages: 600-602
  • Peer Reviewed
• [Journal Article] Organ-Specific Sulfation Patterns of Heparan Sulfate Generated by Extracellular Sulfatases Sulf1 and Sulf2 in Mice. (2012)
  • Author(s): Nagamine, S., Tamba, M., Ishimine, H., Araki, K., Shiomi, K., Okada, T., Ohto, T., Kunita, S., Takahashi, S., Wismans, R.G.P., van Kuppevelt, T.H., Masu, M., and Keino-Masu, K.
  • Journal Title: Journal of Biological Chemistry Volume: 287 Pages: 9579-9590
  • DOI: 10.1074/jbc.m111.290262
  • NAID: 120007130630
  • Peer Reviewed
• [Journal Article] Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis. (2012)
  • Author(s): Nikitopoulou, I., Oikonomou, N., Karouzakis, E., Sevastou, I., Nikolaidou-Katsaridou, N., Zhao, Z., Mersinias, V., Armaka, M., Xu, Y., Masu, M., Mills, G. B., Gay, S., Aidinis, V.
  • Journal Title: Journal of Experimental Medicine Volume: 209 Pages: 925-933
  • DOI: 10.1084/jem.20112012
  • Peer Reviewed
• [Journal Article] Organ-Specific Sulfation Patterns of Heparan Sulfate Generated by Extracellular Sulfatases Sulf1 and Sulf2 in Mice (2012)
  • Author(s): Nagamine, S., Tamba, M., Ishimine, H., Araki, K., Shiomi, K., Okada, T., Ohto, T., Kunita, S., Takahashi, S., Wismans, R.G.P., van Kuppevelt, T.H., Masu, M., Kazuko Keino-Masu
  • Journal Title: Journal of Biological Chemistry Volume: 287 Pages: 9579-9590
  • NAID: 120007130630
  • Peer Reviewed
• [Journal Article] Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis (2012)
  • Author(s): Nikitopoulou, I., Oikonomou, N., Karouzakis, E., Sevastou, I., Nikolaidou-Katsaridou, N., Zhao, Z., Mersinias, V., Armaka, M., Xu, Y., Masu, M., Mills, G.B., Gay, S., Kollias, G., Vassilis Aidinis
  • Journal Title: Journal of Experimental Medicine Volume: (In press)
  • Peer Reviewed
• [Journal Article] Autotaxin is required for the cranial neural tube closure and establishment of the midbrain-hindbrain boundary during mouse development (2011)
  • Author(s): Koike, S., Yutoh, Y., Keino-Masu, K., Noji, S., Masu, M., Ohuchi, H.
  • Journal Title: Developmental Dynamics Volume: 240 Pages: 413-421
  • Peer Reviewed
• [Journal Article] Crystallographic characterization of the DIX domain of the Wnt signalling positive regulator Ccd1 (2011)
  • Author(s): Terawaki, S., Yano, K., Katsutani, T., Shiomi, K., Keino-Masu, K., Masu, M., Shomura, Y., Komori, H., Shibata, N., Higuchi, Y.
  • Journal Title: Acta Crystallographica Section F Volume: 67 Pages: 758-761
  • Peer Reviewed
• [Journal Article] Impaired vascular remodeling in the yolk sac of embryos deficient in ROCK-I and ROCK-II (2011)
  • Author(s): Kamijo, H., Matsumura, Y., Thumkeo, D., Koike, S., Masu, M., Shimizu, Y., Ishizaki, T., Narumiya, S.
  • Journal Title: Genes to Cells Volume: 16 Pages: 1012-1021
  • Peer Reviewed
• [Journal Article] Autotaxin is required for the cranial neural tube closure and establishment of the midbrain-hindbrain boundary during mouse development. (2011)
  • Author(s): Koike, S., Yutoh, Y., Keino-Masu, K., Noji, S., Masu, M., Ohuchi, H.
  • Journal Title: Dev.Dyn. Volume: 240 Pages: 413-421
  • Peer Reviewed
• [Journal Article] Proteolytic cleavage of the rat heparan sulfate 6-O-endosulfatase SulfFP2 by furin-type proprotein convertases. (2010)
  • Author(s): Nagamine, S., Keino-Masu, K., Shiomi, K., Masu, M.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 391 Pages: 107-112
  • Peer Reviewed
• [Journal Article] Deficiency of autotaxin/lysophospholipase D results in head cavity formation in mouse embryos through the LPA receptor-Rho-ROCK pathway. (2010)
  • Author(s): Koike, S., Keino-Masu, K., Masu, M.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 400 Pages: 66-71
  • NAID: 120007137917
  • Peer Reviewed
• [Journal Article] Combining the Cell Encapsulation Technique and Axon Guidance for Cell Transplantation Therapy. (2010)
  • Author(s): Yamazoe, H., Keino-Masu, K., Masu, M.
  • Journal Title: J.Biomaterial Sci. Volume: 21 Pages: 1815-1826
  • NAID: 120007137895
  • Peer Reviewed
• [Presentation] ゼブラフィッシュCCD1 DIXドメインのX線結晶解析X-ray crystallographic analysis of zebrafish CCD1 DIX domain (2015)
  • Author(s): 藤田祥平、寺脇慎一、塩見健輔、桝和子、桝正幸、若松馨、柴田直樹、樋口芳樹
  • Organizer: 第32回PFシンポジウム
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2015-03-17 – 2015-03-18
• [Presentation] Analysis of the corticospinal tract formation in adult Sulf1;Sulf2 double knockout mice (2014)
  • Author(s): Takuya Okada, Nana Kagaya, Kazuko Keino-Masu, Masayuki Masu
  • Organizer: 第37回日本神経科学学会大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-14
• [Presentation] Electron microscopic observation of intranuclear aggregation of TDP-43 in mouse cerebral cortex produced by in utero electroporation (2014)
  • Author(s): Megumi Akamatsu, Hiroshi Takuma, Takenari Yamashita, Takuya Okada, Kazuko Keino-Masu, Hartmut Oehring, Shin Kwak, Masayuki Masu, Gustav F Jirikowski, Akira Tamaoka
  • Organizer: 第37回日本神経科学学会大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-14
• [Presentation] 子宮内電気穿孔法TDP-43 遺伝子導入によるin vivo形成封入体の微細形態の検討 (2014)
  • Author(s): 詫間浩、赤松恵、山下雄也、Oehring, H.、岡田拓也、桝和子、石井一弘、Jirikowski, G、郭伸、桝正幸、玉岡晃
  • Organizer: 第55回日本神経学会総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] Heparan sulfate modification by endosulfatases Sulf1 and Sulf2 is required for the cotricospinal tract formation (2014)
  • Author(s): Kazuko Keino-Masu, Takuya Okada, Masayuki Masu.
  • Organizer: International Symposium on Glyco-Neuroscience
  • Place of Presentation: Awaji Yumebutai International Conference Center（Hyogo）
• [Presentation] ヘパラン硫酸エンドスルファターゼSulf1の嗅覚記憶における役割 (2013)
  • Author(s): 桝和子、奥谷文乃、椛秀人、桝正幸
  • Organizer: 第36回日本神経科学学会大会・第56回日本神経化学会大会・第30回日本神経回路学会大会
  • Place of Presentation: 国立京都国際会館（京都）
• [Presentation] マウス胎仔電気穿孔法による in vivo TDP-43 遺伝子導入と封入体形成の検討 (2013)
  • Author(s): 詫間浩、赤松恵、山下雄也、岡田拓也、石井一弘、桝和子、郭伸、桝正幸、玉岡晃
  • Organizer: 第54回日本神経学会総会
  • Place of Presentation: 東京国際フォーラム（東京）
• [Presentation] 筋萎縮性側索硬化症関連タンパク：TDP-43封入体の形成-マウス胎児電気穿孔法による大脳皮質運動野への疾患関連遺伝子の導入 (2013)
  • Author(s): 赤松恵、詫間浩、山下雄也、岡田拓也、石井一弘、桝和子、郭伸、桝正幸、玉岡晃
  • Organizer: 第36回日本神経科学学会大会・第56回日本神経化学会大会・第30回日本神経回路学会大会
  • Place of Presentation: 国立京都国際会館（京都）
• [Presentation] Ccd1/Dixdc1欠損マウスにおける行動異常 (2013)
  • Author(s): 桝正幸、昌子浩孝、塩見健輔、宮川剛、桝和子
  • Organizer: 第36回日本神経科学学会大会・第56回日本神経化学会大会・第30回日本神経回路学会大会
  • Place of Presentation: 国立京都国際会館（京都）
• [Presentation] Extracellular sulfatases regulate PDGF signaling and promotes nephropathy in diabetes. (2013)
  • Author(s): Takashima, Y., Yashiro, H., Masu, M. Keino-Masu, K., and Nagata, M.
  • Organizer: Kidney week 2012
  • Place of Presentation: Atlanta, USA
  • Invited
• [Presentation] Role of podocyte extracellular sulfatase in regulation of glomerular permeability. (2012)
  • Author(s): Takashima, Y., Yamashita, H., Sakamoto, K., Hara, S., Kobayashi, N., Ueno, T., Keino-Masu, K., Masu, M. and Nagata, M.
  • Organizer: Kidney week 2012
  • Place of Presentation: San Diego Convention Center（米国）
  • Year and Date: 2012-10-30
• [Presentation] Heparan Sulfate Modification by Endosulfatases is Required for Cortical Axon Guidance (2012)
  • Author(s): Masayuki Masu, Takuya Okada, Satoshi Nagamine, Tatsuyuki Ohto, Fuyuki Kametani, Masato Hasegawa, Satoshi Kunita, Satoru Takahashi, Kazuko Keino-Masu
  • Organizer: 1^<st> international symposium/59^<th> NIBB conferences "Neocortical organization"
  • Place of Presentation: 岡崎カンファレンスセンター(岡崎)(招待講演)
• [Presentation] ヘパラン硫酸糖鎖による軸索ガイダンス制御機構 (2011)
  • Author(s): 桝正幸、岡田拓也、長嶺聖史、大戸達之、亀谷富由樹、長谷川成人、國田智、高橋智、桝和子
  • Organizer: 第34回日本神経科学学会大会
  • Place of Presentation: パシフィコ横浜(横浜)(招待講演)
• [Presentation] The roles of heparan sulfate in axon guidance (2010)
  • Author(s): 桝正幸
  • Organizer: International Graduate Schools International Conference
  • Place of Presentation: つくば国際会議場(茨城)
  • Year and Date: 2010-11-01
• [Presentation] Wntシグナル伝達機構ではたらくCCD1の構造化学的研究 (2010)
  • Author(s): 寺脇慎一、塩見健輔、桝正幸、柴田直樹、樋口芳樹
  • Organizer: 第10回日本蛋白質科学会年会
  • Place of Presentation: 札幌コンベンションセンター(北海道)
• [Presentation] マウス胎児脳におけるヘパラン硫酸多様性の検出 (2010)
  • Author(s): 岡田拓也、桝和子、長嶺聖史、國田智、高橋智、Arie Oosterhof, Toin Kuppevelt、桝正幸
  • Organizer: 第33回日本神経科学学会大会・第53回日本神経化学会大会・第20回日本神経回路学会大会
  • Place of Presentation: 神戸コンベンションセンター(兵庫)
• [Presentation] Wntシグナル伝達で機能するCCD1オリゴマー形成機構に関する構造学的研究 (2010)
  • Author(s): 寺脇慎一、塩見健輔、桝正幸、柴田直樹、樋口芳樹
  • Organizer: 日本結晶学会2010年年会
  • Place of Presentation: 大阪大学コンベンションセンター(大阪)
• [Presentation] Heparan sulfate 6-Oendosulfatases are required for neural network formation. (2010)
  • Author(s): T.Okada, K.Keino-Masu, S.Nagamine, S.Kunita, S.Takahashi, M.Masu
  • Organizer: The 40th Annual meeting of the Society for Neuroscience
  • Place of Presentation: San Diego, convenction center(米国)
• [Presentation] Wntシグナル伝達で機能するCCD1 DIXドメインのX線結晶構造解析 (2010)
  • Author(s): 寺脇慎一、塩見健輔、桝正幸、柴田直樹、樋口芳樹
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会
  • Place of Presentation: 神戸国際会議場(兵庫)
• [Presentation] Autotaxin is required for anterior neural ridge formation, midbrain-hindbrain boundary patterning, and cranial neural tube closure. (2010)
  • Author(s): E.Tagiuchi, S.Koike, Y.Yutoh, K.Keino-Masu, S.Noji, M.Masu, H.Ohuchi.
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会
  • Place of Presentation: 神戸国際会議場(兵庫)
• [Presentation] TDP-43 aggregation produced by In utero electroporation and its properties in the mouse motor neurons
  • Author(s): Akamatsu, M., Takuma, H., Yamashita, T., Okada, T., Ishii, K., Keino-Masu, K., Kwak, S., Masu, M., Tamaoka, A.
  • Organizer: 43th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego Convention Center, San Diego, USA
• [Book] Cortical Development: Neural Diversity and Neocortical Organization (2013)
  • Author(s): Masu, M.
  • Total Pages: 320
  • Publisher: Springer-Verlag
• [Book] Lysophospholipid Receptors: Signaling and Biochemistry. (2013)
  • Author(s): Masu, M., Koike, S., Okada, T., and Keino-Masu, K.
  • Total Pages: 812
  • Publisher: John Wiley & Son Inc
• [Book] Lysophospholipid Receptors: Signaling and Biochemistry (2013)
  • Author(s): Masu, M., Koike, S., Okada, T., and Keino-Masu, K.
  • Publisher: John Wiley Son Inc.
• [Remarks]
  • URL: http://www.md.tsukuba.ac.jp/duo/molneurobiol/
• [Remarks]
  • URL: http://www.md.tsukuba.ac.jp/duo/molneurobiol/
• [Remarks]
  • URL: http://www.md.tsukuba.ac.jp/duo/molneurobiol/
• [Remarks]
  • URL: http://www.md.tsukuba.ac.jp/basic-med/molneurobiol/index.html