Re-evaluation of DISC1 using knockout mice and new antibodies

• Project/Area Number: 25830051
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Nagoya University
• Principal Investigator: KURODA Keisuke 名古屋大学, 医学(系)研究科(研究院), 特任助教 (80631431)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: DISC1 / 統合失調症 / モデルマウス / ノックアウトマウス / 抗体 / オフターゲット / プロテオミクス解析 / シナプス / リン酸化 / 分子機能 / 活性制御機構

Outline of Final Research Achievements

Disrupted-In-Schizophrenia 1 (DISC1) is a promising candidate gene for susceptibility to psychiatric disorders, including schizophrenia. We previously generated a DISC1 knockout (KO) mouse and developed DISC1 antibodies. We found that no available antibodies to DISC1 without us recognized the endogenous DISC1. The DISC1 KO mouse displays no gross abnormalities, but it does show altered synaptic plasticity and abnormal emotional behaviors. So that we re-evaluate DISC1 using KO mice and new antibodies and investigate true function of DISC1 in synapse.
We found that cell migration defect coused by DISC1 knockdown is an off-target effect of shRNA. This result suggests that DISC1 studies using DISC1 shRNAs should be interpreted with caution.
We used proteomic analysis to screen for DISC1 interactors and identified several RNA-binding proteins. We found that DISC1 binds ITPR1 mRNA with HZF, thereby regulating its dendritic transport for synaptic plasticity.

Research Products

• [Journal Article] Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. (2015)
  • Author(s): Tsuboi D, Kuroda K, Tanaka M, Namba T, Iizuka Y, Taya S, Shinoda T, Hikita T, Muraoka S, Iizuka M, Nimura A, Mizoguchi A, Shiina N, Sokabe M, Okano H, Mikoshiba K, Kaibuchi K
  • Journal Title: Nature Neuroscience Volume: in press Issue: 5 Pages: 698-707
  • DOI: 10.1038/nn.3984
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Disrupted-in-schizophrenia-1 (DISC1) Regulates Endoplasmic Reticulum Calcium Dynamics. (2015)
  • Author(s): Park SJ, Jeong J, Park YU, Park KS, Lee H, Lee N, Kim SM, Kuroda K, Nguyen MD, Kaibuchi K, Park SK.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 8694-8694
  • DOI: 10.1038/srep08694
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Alterations of GABAergic and dopaminergic system in mutant mice with disruption of exons 2 and 3 of the Disc1 gene. (2014)
  • Author(s): Nakai T, Nagai T, Wang R, Yamada S, Kuroda K, Kaibuchi K, Yamada K
  • Journal Title: Neurochem. Int. Volume: 74 Pages: 74-83
  • DOI: 10.1016/j.neuint.2014.06.009
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neuronal PAS domain domain protein 4 (Npas4) regulates neurite outgrowth and phosphorylation of synapsin I. (2013)
  • Author(s): Yun J, Nagai T, Furukawa-Hibi Y, Kuroda K, Kaibuchi K, Greenberg ME, and Yamada K
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 4 Pages: 2655-2664
  • DOI: 10.1074/jbc.m112.413310
  • Peer Reviewed
• [Remarks] 2015.03.31. 統合失調症モデルマウスを用いた解析で新たな統合失調症病態シグナルを同定
  • URL: http://www.med.nagoya-u.ac.jp/medical/dbps_data/_material_/nu_medical/_res/topix/2014/itpr1_20150331jp.pdf
• [Remarks] 新規抗DISC1抗体の市販化
  • URL: http://www.millipore.com/catalogue/item/abn425