Functional analysis of MDGA family proteins on neural circuit formation of cerebral cortex.

• Project/Area Number: 25460059
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Kagawa University
• Principal Investigator: Yamamoto Tohru 香川大学, 医学部, 教授 (10251480)
• Research Collaborator: Craig Ann Marie The University of British Columbia, Neurobiology Research Centre, Professor & Canada Research Chair
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 自閉症スペクトラム障害 / 統合失調症 / MDGA1 / MDGA2 / Neuroligin / シナプス形成 / Ｅ/Ｉバランス / E/Iバランス / ニューロリギン / 自閉症スペクトラム / 行動異常 / 大脳皮質 / 自閉症 / 行動解析

Outline of Final Research Achievements

Mdga1 encodes a GPI-anchored IgSF protein, which we isolated as a gene expressed by a specific subset of neurons. In mouse coticogenesis, Mdga1 is selectively expressed by the upper layer neurons, while the other family member Mdga2 is widely expressed in a brain. We previously showed that Mdga1 is required for proper radial migration of a subset of upper-layer neurons; however, the resultant layer structure becomes apparently normal. We further investigated the function of MDGA family proteins in postnatal brain function since expression of Mdga1/2 persists throughput the life. It was shown that MDGA1/2 directly interact with Neuroligin family molecules to inhibit their binding to Neurexin, and we found that MDGA1 deficient mice showed more inhibitory synapses and MDGA2 +/- mice showed more excitatory synapses in their cortexes to exhibit behavioral abnormality related to schizophrenia or ASD, suggesting that MDGAs play an important role for maintaining proper E/I balance in a brain.

Research Products

• [Int'l Joint Research] The University of British Columbia(Canada)
• [Int'l Joint Research] Cincinnati Children's Hospital M.C.(米国)
• [Journal Article] Ryanodine receptors contribute to the induction of ischemic tolerance. (2016)
  • Author(s): Nakamura-Maruyama E, Miyamoto O, Okabe N, Himi N, Feng L, Narita K, Keep RF, Yamamoto T, Nakamura T
  • Journal Title: Brain Research Bulletin Volume: 122 Pages: 45-53
  • DOI: 10.1016/j.brainresbull.2016.02.018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cytoplasmic Fragment of Alcadein α Generated by Regulated Intramembrane Proteolysis Enhances Amyloid β-Protein Precursor (APP) Transport into the Late Secretory Pathway and Facilitates APP Cleavage (2015)
  • Author(s): Norio Takei, Yuriko Sobu, Ayano Kimura, Satomi Urano, Yi Piao, Yoichi Araki, Hidenori Taru, Tohru Yamamoto, Saori Hata, Tadashi Nakaya, Toshiharu Suzuki
  • Journal Title: Journal of Biological Chemistry Volume: 290 Issue: 2 Pages: 987-995
  • DOI: 10.1074/jbc.m114.599852
  • Peer Reviewed / Open Access
• [Journal Article] Increased levels of plasma p3-Alcα35, a major fragment of Alcadeinα by γ-secretase cleavage, in Alzheimer's disease (2014)
  • Author(s): Omori C, Kaneko M, Nakajima E, Akatsu H, Waragai M, Maeda M, Moroshima-Kawashima M, Saito Y, Nakaya T, Taru H, Yamamoto T, Asada T, Hata S, Suzuki T. for J-ADNI
  • Journal Title: J. Alzheimers Dis Volume: 39 Issue: 4 Pages: 861-870
  • DOI: 10.3233/jad-131610
  • Peer Reviewed
• [Journal Article] Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport. (2014)
  • Author(s): Chiba K, Araseki M, Nozawa K, Furukori K, Araki Y, Matsushima T, Nakaya T,Hata S, Saito Y, Uchida S, Okada Y, Nairn AC, Davis RJ, Yamamoto T, Kinjo M, Taru, H, Suzuki T.
  • Journal Title: Mol Biol Cell Volume: 25 Issue: 22 Pages: 3569-3580
  • DOI: 10.1091/mbc.e14-06-1111
  • NAID: 120005522339
  • Peer Reviewed / Open Access
• [Journal Article] Ameliorative effects of yokukansan on behavioral deficits in a gerbil model of global cerebral ischemia. (2014)
  • Author(s): Yanan Liu
  • Journal Title: Brain Res. Volume: 1543 Pages: 300-307
  • DOI: 10.1016/j.brainres.2013.11.015
  • Peer Reviewed
• [Journal Article] Mechanism of intramembrane cleavage of Alcadeins by γ-secretase (2013)
  • Author(s): Piao, Y., Kimura, A., Urano, S., Saito, Y., Taru, H., Yamamoto, T., Hata, S. and Suzuki, T
  • Journal Title: PLoS One Volume: 8 Issue: 4 Pages: e62431-e62431
  • DOI: 10.1371/journal.pone.0062431
  • Peer Reviewed
• [Presentation] アルカデインはX11Lと協働して内在性APPのアミロイド産生的代謝を抑制する (2015)
  • Author(s): 山本 融 後藤 直也 齋藤 有紀 村山 千明 鈴木 利治
  • Organizer: 第38回分子生物学会年会・第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-01
• [Presentation] 大脳新皮質形成時における放射状細胞移動の細胞種による多様性 (2015)
  • Author(s): 尾嶋 大喜 山本 融
  • Organizer: 第38回分子生物学会年会・第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-01
• [Presentation] JIP1を介したAPP軸索順行輸送の制御機構解析 (2015)
  • Author(s): 加藤 優実 千葉 杏子 山本 融 鈴木 利治
  • Organizer: 第38回分子生物学会年会・第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-01
• [Presentation] Absence of MDGA1 Enhances Inhibitory Drive and Confers Resistance to Increased Excitation in Mouse Hippocampus (2015)
  • Author(s): Steven A. Connor, Ina Ammendrup-Johnsen, Parisa Karimi Tari, Tohru Yamamoto, Yu Tian Wang, and Ann Marie Craig
  • Organizer: 9th Annual Canadian Neuroscience Meeting
  • Place of Presentation: Westin Bayshore, Vancouver, Canada
  • Year and Date: 2015-05-24
• [Presentation] Alcadein drives kinesin-1 and undergoes constitutive limited proteolysis to maintain proper distribution of kineisn-1. (2014)
  • Author(s): 山本融 豊島哲彦 丸田千明 荒関雅彦 鈴木利治
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Ameliorative effects of Yokukansan on behavioral deficits following transient forebrain ischemia in gerbils (2014)
  • Author(s): 劉亜南 中村丈洋 豊島哲彦 山本融 板野俊文
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13