大脳新皮質の層構造と機能

2010 Fiscal Year Annual Research Report

• Project Area: Neural Diversity and Neocortical Organization
• Project/Area Number: 22123008
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Research Institution: The University of Tokyo
• Principal Investigator: 三品 昌美 東京大学, 大学院・医学系研究科, 教授 (80144351)
• Keywords: 神経科学 / 脳神経疾患 / 遺伝子 / 大脳新皮質 / IL1RAPL1 / PTPδ / シナプス形成 / 精神遅滞

Research Abstract

大脳新皮質第4層特異的Eag2遺伝子に誘導型CrePR遺伝子を挿入したマウスを標的遺伝子組換えにより作成した。さらに、Eag2-CrePRマウスをCre依存的にジフテリア毒素Aを発現するNSE-DTAマウスと掛け合わせ、RU-486の投与によりCrePRの組換え酵素を活性化し、大脳新皮質第4層の神経細胞が誘導除去されることを示した。平行して、大脳新皮質第5層特異的に発現するFezf2遺伝子にCre遺伝子を挿入した標的遺伝子組換えベクターを構築した。また、精神遅滞と自閉症の原因分子である膜蛋白質インターロイキン-1レセプターアクセサリープロテインライク1(IL1RAPL1)が培養大脳神経細胞においてシナプス形成を誘導することを見いだした。シナプス形成誘導能は興奮シナプス特異的であり、IL1RAPL1の細胞外領域が重要であることを明らかにした。IL1RAPL1の細胞外領域に結合する分子を探索し、神経細胞のシナプス後部に存在する膜蛋白質IL1RAPL1が連結する相手の神経細胞のシナプス前部に存在する膜蛋白質受容体型チロシン脱リン酸化酵素(PTP)δと互いに結合することにより、神経細胞間のシナプス形成を促進することを見出した。これらの成果から、IL1RAPL1の欠損が脳神経ネットワーク形成の不全を引き起こし、精神遅滞と自閉症の引き金となっていると考えられる。今回の発見は、シナプス形成の障害が精神疾患を引き起こす経路となることを示唆している。さらに、精神遅滞原因遺伝子IL1RAPL1を欠損させる標的遺伝子組換えベクターを構築し、欠損マウスを作製した。

Research Products

• [Journal Article] Identification and characterization of a novel zebrafish semaphorin (2011)
  • Author(s): Taniguchi, M., Masuda, T., Mikami, Y., Kimura, M., Yoshida, T., Mishina, M., Shimizu, T.
  • Journal Title: Neurosci.Lett. Volume: 488 Pages: 215-220
  • Peer Reviewed
• [Journal Article] NR3A-containing NMDA receptors promote neurotransmitter release and spike timing-dependent plasticity (2011)
  • Author(s): Larsen, R.S., Corlew, R.J., Henson, M.A., Roberts, A.C., Mishina, M., Watanabe, M., Lipton, S.A., Nakanishi, N., Perez-Otano, I., Weinberg, R.J., Philpot, B.D.
  • Journal Title: Nature Neurosci. Volume: 14 Pages: 338-344
  • Peer Reviewed
• [Journal Article] Glutamate receptor δ2 is essential for input pathway-dependent regulation of synaptic AMPAR contents in cerebellar Purkinje cells (2011)
  • Author(s): Yamasaki, M., Miyazaki, T., Azechi, H., Abe, M., Natsume, R., Hagiwara, T., Aiba, A., Mishina, M., Sakimura, K., Watanabe, M.
  • Journal Title: J.Neurosci. Volume: 31 Pages: 3362-3374
  • Peer Reviewed
• [Journal Article] Differential interactions of cerebellin precursor protein (Cbln) subtypes and neurexin variants for synapse formation of cortical neurons (2011)
  • Author(s): Joo, J., Lee, S., Uemura, T., Yoshida, T., Yasumura, M., Watanabe, M., Mishina, M.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 406 Pages: 627-632
  • Peer Reviewed
• [Journal Article] Remodeling of monoplanar Purkinje cell dendrites during cerebellar circuit formation (2011)
  • Author(s): Kaneko, M., Yamaguchi, K., Eiraku, M., Sato, M., Takata, N., Kiyohara, Y., Mishina, M., Hirase, H., Hashikawa, T., Kengaku, M.
  • Journal Title: PLoS ONE Volume: 6(E-pub) Pages: e20108
  • Peer Reviewed
• [Journal Article] IL1RAPL1 associated with mental retardation and autism mediates synapse formation by trans-synaptic interaction with PTPδ (2011)
  • Author(s): Yoshida, T., Yasumura, M., Uemura, T., Lee, S., Ra, M., Taguchi, R., Iwakura, Y., Mishina, M.
  • Journal Title: J.Neurosci. Volume: 31 Pages: 13485-13499
  • Peer Reviewed
• [Journal Article] Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability (2010)
  • Author(s): Mozhui, K., Karlsson, R-M., Kash, T.L., Ihne, J., Norcross, M., Patel, S., Farrell, M.R., Hill, E., Martin, K., Camp, M., Fitzgerald, P.J., Ciobanu, D.C., Sprengel, R., Mishina, M., Wellman, C.L., Winder, D.G., Williams, R.W., Holmes, A.
  • Journal Title: J.Neurosci. Volume: 30 Pages: 5357-5367
  • Peer Reviewed
• [Journal Article] Trans-synaptic interaction of GluRδ2 and neurexin through Cbln1 mediates synapse formation in the cerebellum (2010)
  • Author(s): Uemura, T., Lee, S., Yasumura, M., Takeuchi, T., Yoshida, T., Ra, M., Taguchi, R., Sakimura, K., Mishina, M.
  • Journal Title: Cell Volume: 141 Pages: 1068-1079
  • Peer Reviewed
• [Journal Article] Specific involvement of postsynaptic GluRN2B-containing NMDA receptors in the developmental elimination of corticospinal synapses (2010)
  • Author(s): Ohno, T., Maeda, H., Murabe, N., Kamiyama, T., Yoshioka, N., Mishina, M., Sakurai, M.
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: 107 Pages: 15252-15257
  • Peer Reviewed
• [Journal Article] Essential role of NMDA receptor channel ε4 subunit (GluN2D) in the effects of phencyclidine, but not methamphetamine (2010)
  • Author(s): Hagino, Y., Kasai, S., Han, W., Yamamoto, H., Nabeshima, T., Mishina, M., Ikeda, K.
  • Journal Title: PLoS ONE Volume: 5(E-pub) Pages: e13722
  • Peer Reviewed
• [Journal Article] Ablation of glutamate receptor GluRδ2 in adult Purkinje cells causes multiple innervation of climbing fibers by inducing a berrant invasion to parallel fiber innervation territory (2010)
  • Author(s): Miyazaki, T., Yamasaki, M., Takeuchi, T., Sakimura, K., Mishina, M., Watanabe, M.
  • Journal Title: J.Neurosci. Volume: 30 Pages: 15196-15209
  • Peer Reviewed
• [Journal Article] The physiological roles of vesicular GABA transporter during embryonic development : a study using knockout mice (2010)
  • Author(s): Hayashi, R., Nakazato, Y., Takamori, S., Ebihara, S., Uematsu, M., Mishina, M., Miyazaki, J., Yokoyama, M., Konishi, S., Inoue, K., Fukuda, A., Fukumoto, M., Nakamura, K., Obata, K., Yanagawa, Y.
  • Journal Title: Mol.Brain Volume: 3(E-pub) Pages: 40
  • Peer Reviewed
• [Presentation] Identification of a novel ligand for glutamate receptor δ2 (2010)
  • Author(s): Mishina, M., Uemura, T., Lee, S., Yasumura, M., Yoshida, T.
  • Organizer: The 16th World Congress of Basic and Clinical Pharmacology
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2010-07-22