Molecular mechanism of autism caused by gene abnormalities of the clock genes

• Project/Area Number: 16H05363
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Institute for Developmental Research Aichi Developmental Disability Center
• Principal Investigator: Nagata Koh-ichi 愛知県医療療育総合センター発達障害研究所, 分子病態研究部, 部長 (50252143)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2016: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 自閉性障害 / 時計遺伝子 / 大脳皮質発生 / 神経細胞 / PER3 / 発達障害 / 大脳皮質 / 自閉症 / 大脳皮質形成 / シナプス / 遺伝子 / 遺伝子変異 / NR1D1 / TIMELESS / 概日リズム異常

Outline of Final Research Achievements

Functional and structural defects in neuronal synapses are thought to underlie the pathophysiology of autism spectrum disorders (ASD). While more than 50 % of ASD patients suffer from sleep disturbance, relationship between circadian rhythm and ASD etiology is largely unknown. In this study, we focused on 3 circadian clock genes, TIMELESS, NR1D1 and PER3, whose gene abnormalities have been reported in ASD individuals. By the use of mouse models produced by "comprehensive in vivo/in vitro analytical battery" we constructed, we analyzed pathophysiological significance of gene abnormalities of TIMELESS, NR1D1 and PER3 in ASD.

Academic Significance and Societal Importance of the Research Achievements

本研究は、概日リズム障害（時計遺伝子の機能障害）の観点からASDの大脳皮質形成障害・シナプス病態に迫り、新しい病態形成メカニズムの発見を目指した。この着想の発端は、ASD患者の遺伝子解析で、時計遺伝子TIMELESS, NR1D1 and PER3に新規ミスセンス変異を発見したことにある。これらの変異が大脳皮質形成とシナプス動態に与える影響をin vivo/in vitroで包括的に解析した結果、ASDの新たな病態メカニズムの存在が示唆された。

Research Products

• [Int'l Joint Research] Dept. of Pharmacology, Yale University(米国)
• [Journal Article] Biochemical and Morphological Characterization of a Guanine Nucleotide Exchange Factor ARHGEF9 in Mouse Tissues (2018)
  • Author(s): Ibaraki Kyoko、Mizuno Makoto、Aoki Hitomi、Niwa Ayumi、Iwamoto Ikuko、Hara Akira、Tabata Hidenori、Ito Hidenori、Nagata Koh-ichi
  • Journal Title: ACTA HISTOCHEMICA ET CYTOCHEMICA Volume: 51 Issue: 3 Pages: 119-128
  • DOI: 10.1267/ahc.18009
  • NAID: 130007411561
  • ISSN: 0044-5991, 1347-5800
  • Year and Date: 2018-06-26
  • Peer Reviewed
• [Journal Article] Expression analyses of Dusp22 (Dual-specificity phosphatase 22) in mouse tissues. (2018)
  • Author(s): Hamada N, Mizuno M, Tomita H, Iwamoto I, Hara A, Nagata K
  • Journal Title: Med. Mol. Morphol. Volume: 51 Issue: 2 Pages: 111-117
  • DOI: 10.1007/s00795-017-0178-3
  • Peer Reviewed
• [Journal Article] Expression analyses of Phactr1 (phosphatase and actin regulator 1) during mouse brain development. (2018)
  • Author(s): Ito H, Mizuno M, Noguchi K, Morishita R, Iwamoto I, Hara A, Nagata K.
  • Journal Title: Neurosci Res Volume: 128 Pages: 50-57
  • DOI: 10.1016/j.neures.2017.08.002
  • Peer Reviewed
• [Journal Article] A Prdm8 target gene Ebf3 regulates multipolar-to-bipolar transition in migrating neocortical cells (2018)
  • Author(s): Iwai Ryota、Tabata Hidenori、Inoue Mayuko、Nomura Kei-ichiro、Okamoto Tadashi、Ichihashi Masamitsu、Nagata Koh-ichi、Mizutani Ken-ichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 1 Pages: 388-394
  • DOI: 10.1016/j.bbrc.2017.11.021
  • Peer Reviewed / Open Access
• [Journal Article] Possible involvement of a cell adhesion molecule, Migfilin, in brain development and pathogenesis of autism spectrum disorders (2017)
  • Author(s): Ishizuka Kanako、Tabata Hidenori、Ito Hidenori、Kushima Itaru、Noda Mariko、Yoshimi Akira、Usami Masahide、Watanabe Kyota、Morikawa Mako、Uno Yota、Okada Takashi、Mori Daisuke、Aleksic Branko、Ozaki Norio、Nagata Koh-ichi
  • Journal Title: Journal of Neuroscience Research Volume: 96 Issue: 5 Pages: 789-802
  • DOI: 10.1002/jnr.24194
  • Peer Reviewed / Open Access
• [Journal Article] Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders. (2017)
  • Author(s): Goto, M., Mizuno, M., Matsumoto, A., Yang, Z., Jimbo, E.F., Tabata, H., Yamagata, T., Nagata, K.-I.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 43945-43945
  • DOI: 10.1038/srep43945
  • Peer Reviewed / Open Access
• [Journal Article] Role of a heterotrimeric G-protein, Gi2, in the corticogenesis: possible involvement in periventricular nodular heterotopia and intellectual disability. (2016)
  • Author(s): Hamada, N., Negishi, Y., Mizuno, M., Miya, F., Hattori, A., Okamoto, N., Kato, M., Tsunoda, T., Yamasaki, M., Kanemura, Y., Kosaki, K., Tabata, H., Saitoh, S., Nagata, K.-I.
  • Journal Title: J. Neurochem. Volume: 140 Issue: 1 Pages: 82-95
  • DOI: 10.1111/jnc.13878
  • Peer Reviewed
• [Journal Article] Morphological characterization of Class III phosphoinositide 3-kinase during mouse brain development. (2016)
  • Author(s): Inaguma Y, Ito H, Iwamoto I, Matsumoto A, Yamagata T, Tabata H, Nagata K-I
  • Journal Title: Med Mol Morphol Volume: 49 Issue: 1 Pages: 28-33
  • DOI: 10.1007/s00795-015-0116-1
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of BDNF exocytosis and GABAergic interneuron synapse by the schizophrenia susceptibility gene dysbindin-1. (2016)
  • Author(s): Yuan Q, Yang F, Xiao Y, Tan S, Husain N, Ren M, Hu Z, Martinowich K, Ng J S, Kim P J, Han W, Nagata K, Weinberger DR, H. Je S
  • Journal Title: Biol. Psychiatry Volume: 80 Issue: 4 Pages: 312-322
  • DOI: 10.1016/j.biopsych.2015.08.019
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients. (2016)
  • Author(s): Yang Z, Matsumoto A, Nakayama K, Jimbo F E, Kojima K, Nagata K, Iwamoto S, Yamagata T
  • Journal Title: Brain & Dev. Volume: 38 Pages: 91-99
  • Peer Reviewed
• [Journal Article] Role of Class III phosphoinositide 3-kinase in the brain development: possible involvement in specific learning disorders. (2016)
  • Author(s): Inaguma Y, Matsumoto A, Noda M, Tabata H, Maeda A, Goto M, Usui D, Jimbo EF, Kikkawa K, Ohtsuki M, Momoi MY, Osaka H, Yamagata T, Nagata KI
  • Journal Title: J Neurochem Volume: 139 Issue: 2 Pages: 245-55
  • DOI: 10.1111/jnc.13832
  • Peer Reviewed
• [Presentation] Comprehensive analyses of causative genes for ASD with in utero electropolation technique. (2017)
  • Author(s): Nagata K
  • Organizer: International Symposium on Autism 2017
  • Int'l Joint Research / Invited
• [Presentation] Comprehensive analyses of RBFOX1, a causative gene for neurodevelopmental and psychiatric diseases, in the brain development. (2016)
  • Author(s): Nagata K
  • Organizer: The 14th Meeting of the Asian-Pacific Society for Neurochemistry