Genetic and molecular analyses of causative genes for autism-spectrum disorders

• Project/Area Number: 25670488
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Institute for Developmental Research, Aichi Human Service Center
• Principal Investigator: Nagata Koh-ichi 愛知県心身障害者コロニー発達障害研究所, 神経制御学部, 部長 (50252143)
• Co-Investigator(Kenkyū-buntansha): 山形 崇倫 自治医科大学, 医学部, 教授 (00239857)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 自閉性障害 / 神経細胞 / 大脳皮質構築 / 自閉症 / 大脳皮質形成 / NR1D1 / 大脳皮質 / RBFOX1 / Migfilin / 自閉性疾患 / 神経細胞移動 / 発達障害

Outline of Final Research Achievements

While many different biological causes have been implicated in the etiologies of neurodevelopmental disorders such as autism-spectrum disorder (ASD), genetic factors are considered to be the most important. Thus, it is essential to clarify the pathophysiological significance of respective disease-related genes in brain development. To address this issue, we performed genetic analyses of ASD patients and found a single amino acid mutation in a patient. We then carried out a comprehensive analyses with in utero electroporation including cortical neuron migration, axon elongation, dendrite developmentand live-imaging. Consequently we found abnormal phenotypes in the above analyses.

Research Products

• [Int'l Joint Research] Pohang University(韓国)
• [Int'l Joint Research] Duke-National University of Singapore(Singapore)
• [Journal Article] Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex. (2015)
  • Author(s): Hamada N, Ito H, Iwamoto I, Morishita R, Tabata H, Nagata K-I
  • Journal Title: Molecular Autism Volume: 6 Issue: 1 Pages: 56-56
  • DOI: 10.1186/s13229-015-0049-5
  • Peer Reviewed / Open Access
• [Journal Article] Disrupted-in-schizophrenia 1 (DISC1) regulates dysbindin function by enhancing its stability. (2015)
  • Author(s): Lee S-A, Kim S-M, Suh B K, Sun H-Y, Park Y-U, Hong J-H, Park C, Nguyen M D, Nagata K, Yoo J-Y, Park S K
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 11 Pages: 7087-7096
  • DOI: 10.1074/jbc.m114.614750
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Morphological characterization of mammalian Timeless in the mouse brain development. (2015)
  • Author(s): Inaguma Y, Ito H, Hara A, Iwamoto I, Matsumoto A, Yamagata T, Tabata H, Nagata K.
  • Journal Title: Neurosci Res Volume: 92 Pages: 21-28
  • DOI: 10.1016/j.neures.2014.10.017
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SIL1, a causative cochaperone gene of Marinesco-Sjogren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex. (2014)
  • Author(s): Hamada N, Inaguma Y, Tabata H, Iwamoto I, Mizuno M, Nishimura YV, Ito H, Morishita R, Suzuki M, Ohno K, Kumagai T, Nagata K.
  • Journal Title: EMBO Mol Med. Volume: 6 Issue: 3 Pages: 414-29
  • DOI: 10.1002/emmm.201303069
  • Peer Reviewed / Open Access
• [Journal Article] LIN7A depletion disrupts cerebral cortex development, contributing to intellectual disability in 12q21-deletion syndrome. (2014)
  • Author(s): Matsumoto A, Mizuno M, Hamada N, Nozaki Y, Jimbo E, Momoi M, Nagata K, Yamagata T
  • Journal Title: PLOS ONE Volume: 9 Issue: 3 Pages: e92695-e92695
  • DOI: 10.1371/journal.pone.0092695
  • Peer Reviewed / Open Access
• [Journal Article] Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons. (2014)
  • Author(s): Nishimura YV, Shikanai M, Hoshino M, Ohshima T, Nabeshima Y, Mizutani K, Nagata K, Nakajima K and Kawauchi T
  • Journal Title: Development Volume: 141 Issue: 18 Pages: 3540-3550
  • DOI: 10.1242/dev.111294
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Establishment of an in vivo electroporation method into postnatal newborn neurons in the dentate gyrus. (2014)
  • Author(s): Ito H, Morishita R, Iwamoto I, Nagata K.
  • Journal Title: Hippocampus Volume: 24 Issue: 12 Pages: 1449-1457
  • DOI: 10.1002/hipo.22325
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 自閉性障害の多様な遺伝学的病態とシナプス関連病因遺伝子の解析. (2014)
  • Author(s): 山形崇倫、松本歩、永田浩一
  • Journal Title: 脳と発達 Volume: 46 Pages: 125-130
  • NAID: 130005005694
  • Peer Reviewed
• [Journal Article] Localization of multidomain adaptor proteins, p140Cap and vinexin, in the pancreatic islet of a spontaneous diabetes mellitus model, Otsuka Long-Evans Tokushima Fatty rats. (2013)
  • Author(s): Yamauchi, M.
  • Journal Title: Med. Mol. Morphol. Volume: 46 Issue: 1 Pages: 41-48
  • DOI: 10.1007/s00795-013-0008-1
  • Peer Reviewed
• [Journal Article] Biochemical and morphological characterization of A2BP1 in the neuronal tissue. (2013)
  • Author(s): Hamada N, Ito H, Iwamoto I, Mizuno M, Morishita R, Inaguma Y, Kawamoto S, Tabata H and Nagata K.
  • Journal Title: J Neurosci Res Volume: 91 Issue: 10 Pages: 1303-1311
  • DOI: 10.1002/jnr.23266
  • Peer Reviewed
• [Journal Article] MAGI-1 acts as a scaffolding molecule for NGF receptor-mediated signaling pathway. (2013)
  • Author(s): Ito H, Morishita R, Iwamoto I, Mizuno M, Nagata K
  • Journal Title: Biochim Biophys Acta. Volume: 1833 Issue: 10 Pages: 2302-2310
  • DOI: 10.1016/j.bbamcr.2013.06.005
  • Peer Reviewed
• [Presentation] Comprehensive approach to understand pathophysiological role of SIL1, a gene causing intellectual disability. (2015)
  • Author(s): Nagata K
  • Organizer: 25th Meeting of International Society for Neurochemistry
  • Place of Presentation: Cairns, Australia
  • Year and Date: 2015-08-23
  • Int'l Joint Research / Invited
• [Presentation] Comprehensive approach with an analytical battery to understand pathophysiological role of A2BP1/RBFOX1, a "hub" gene in the ASD gene transcriptome network (2015)
  • Author(s): Koh-ichi Nagata
  • Organizer: Keystone Symposia on Molecular and Cellular Biology
  • Place of Presentation: Tahoe City, California, USA
  • Year and Date: 2015-03-16 – 2015-03-20
  • Invited
• [Presentation] 自閉症スペクトラム障害の病態関連遺伝子の機能解析 (2014)
  • Author(s): 永田浩一
  • Organizer: 第56回日本小児神経学会学術集会シンポジウム
  • Place of Presentation: 浜松
  • Year and Date: 2014-05-29 – 2014-05-31
  • Invited
• [Presentation] Essential role of SIL1, a causative gene of Marinesco-Sjogren syndrome, in the architecture of cerebral cortex during development. (2013)
  • Author(s): Nagata K, Inaguma Y, Nishimura YV, Hamada N, Mizuno M, Ito H, Suzuki M, Hosokawa M, Kumagai T.
  • Organizer: 24th ISN Biennial Meeting
  • Place of Presentation: カンクン国際会議場, Cancun, Mexico
• [Presentation] Possible role of SEPT1 in cancer cell spreading. (2013)
  • Author(s): Nagata K, Mizutani Y, Ito H, Seishima M
  • Organizer: American Society of Cell Biology Meeting
  • Place of Presentation: エルンスト記念会議場、New Orleans, USA
  • Invited
• [Presentation] Biochemical and morphological characterization of an autism-related molecule, A2BP1, in developing cerebral cortex. (2013)
  • Author(s): Nagata K , Hamada N, Ito H, Iwamoto I, Mizuno M, Morishita R, Inaguma Y, Tabata H
  • Organizer: American Society of Cell Biology Meeting
  • Place of Presentation: エルンスト記念会議場、New Orleans, USA
• [Presentation] 自閉性障害の多様な遺伝学的病態とシナプス関連病因遺伝子の解析 (2013)
  • Author(s): 山形崇倫 、松本歩、永田浩一
  • Organizer: 第55回日本小児神経学会学術集会
  • Place of Presentation: いいちこホール（大分県、大分市）
  • Invited
• [Presentation] Biochemical and morphological characterization of A2BP1 in developing cerebral cortex (2013)
  • Author(s): Nagata K , Hamada N, Ito H, Iwamoto I, Mizuno M, Morishita R, Inaguma Y, Tabata H
  • Organizer: Society for Neuroscience Meeting
  • Place of Presentation: サンディエゴ会議センター、San Diego, USA