Molecular pathological analysis of ASD-related gene products in astrocytes

• Project/Area Number: 15K14963
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pharmacology in pharmacy
• Research Institution: Osaka University
• Principal Investigator: Nakazawa Takanobu 大阪大学, 歯学研究科, 准教授 (00447335)
• Co-Investigator(Renkei-kenkyūsha): HASHIMOTO Hitoshi 大阪大学, 大学院薬学研究科, 教授 (30240849) ; HASHIMOTO Ryota 大阪大学, 大学院連合小児発達学研究科, 准教授 (10370983) ; KURIU Toshihiko 徳島文理大学, 薬学部, 講師 (10401374)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 自閉スペクトラム症 / 分子病態 / iPS細胞 / 神経細胞の発達 / ニューロン / アストロサイト / 神経系発達 / iPS細胞関連技術

Outline of Final Research Achievements

The molecular etiology of autism spectrum disorder (ASD) remains poorly understood. Recent studies have found that de novo mutations are likely to be linked to the risk of ASD. Particularly, genes with highly recurrent de novo possible loss-of-function mutations play key roles in ASD. Our laboratory have recently found that several genes, including POGZ and ASD23 have de novo possible ASD-associated mutations. Despite the apparent importance, these mutations have not been functionally analyzed. In this study, we analyzed the functions of these ASD-associated genes as well as the biological significance of these de novo mutations. We found that POGZ regulates neuronal development and that ASD-associated de novo mutations in the POGZ disrupt its DNA-binding activity. Regarding ASD23 gene, we found that ASD23 is highly expressed in astrocytes and regulates neuronal development. These findings provide important insights into the molecular basis of ASD.

Research Products

• [Journal Article] Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia. (2017)
  • Author(s): Kinoshita M, Numata S, Tajima A, Yamamori H, Yasuda Y, Fujimoto M, Watanabe S, Umehara H, Shimodera S, Nakazawa T, Kikuchi M, Nakaya A, Hashimoto H, Imoto I, Hashimoto R, Ohmori T.
  • Journal Title: Int J Mol Sci. Volume: 18 Issue: 3 Pages: 632-632
  • DOI: 10.3390/ijms18030632
  • NAID: 120006535029
  • Peer Reviewed / Open Access
• [Journal Article] Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine. (2017)
  • Author(s): Nakazawa T, Kikuchi M, Ishikawa M, Yamamori H, Nagayasu K, Matsumoto T, Fujimoto M, Yasuda Y, Fujiwara M, Okada S, Matsumura K, Kasai A, Hayata-Takano A, Shintani N, Numata S, Takuma K, Akamatsu W, Okano H, Nakaya A, Hashimoto H, Hashimoto R.
  • Journal Title: Schizophr Res. Volume: 181 Pages: 75-82
  • DOI: 10.1016/j.schres.2016.10.012
  • NAID: 120007037467
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Double In situ Hybridization for MicroRNAs and mRNAs in Brain Tissues. (2016)
  • Author(s): Kasai A, Kakihara S, Miura H, Okada R, Hayata-Takano A, Hazama K, Niu M, Shintani N, Nakazawa T, Hashimoto H.
  • Journal Title: Front Mol Neurosci. Volume: 9 Pages: 126-126
  • DOI: 10.3389/fnmol.2016.00126
  • Peer Reviewed / Open Access
• [Journal Article] Critical involvement of the orbitofrontal cortex in hyperlocomotion induced by NMDA receptor blockade in mice. (2016)
  • Author(s): Seiriki K, Kasai A, Kuwaki T, Nakazawa T, Yamaguchi S, Hashimoto H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 480 Issue: 4 Pages: 558-563
  • DOI: 10.1016/j.bbrc.2016.10.089
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of Brain-Enriched Guanylate Kinase-Associated Protein (BEGAIN) in Chronic Pain after Peripheral Nerve Injury. (2016)
  • Author(s): Katano T, Fukuda M, Furue H, Yamazaki M, Abe M, Watanabe M, Nishida K, Yao I, Yamada A, Hata Y, Okumura N, Nakazawa T, Yamamoto T, Sakimura K, Takao T, Ito S.
  • Journal Title: eNeuro. Volume: 3 Issue: 5 Pages: 0110-16
  • DOI: 10.1523/eneuro.0110-16.2016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prostaglandin D2 signaling mediated by the CRTH2 receptor is involved in MK-801-induced cognitive dysfunction. (2016)
  • Author(s): Onaka Y, Shintani N, Nakazawa T, Kanoh T, Ago Y, Matsuda T, Hashimoto R, Ohi K, Hirai H, Nagata KY, Nakamura M, Kasai A, Hayata-Takano A, Nagayasu K, Takuma K, Ogawa A, Baba A, Hashimoto H.
  • Journal Title: Behav Brain Res. Volume: 314 Pages: 477-486
  • DOI: 10.1016/j.bbr.2016.07.050
  • Peer Reviewed / Open Access
• [Journal Article] De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ. (2016)
  • Author(s): Matsumura K, Nakazawa T, Nagayasu K, Gotoda-Nishimura N, Kasai A, Hayata-Takano A, Shintani N, Yamamori H, Yasuda Y, Hashimoto R, Hashimoto H
  • Journal Title: Journal of Molecular Psychiatry Volume: 印刷中
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders (2016)
  • Author(s): Nakazawa T, Hashimoto R, Sakoori K, Sugaya Y, Tanimura A, Hashimotodani Y, Ohi K, Yamamori H, Yasuda Y, Umeda-Yano S, Kiyama Y, Konno K, Inoue T, Yokoyama K, Inoue T, Numata S, Ohnuma T, Iwata N, Ozaki N, Hashimoto H, Watanabe M, Manabe T, Yamamoto T, Takeda M, Kano M.
  • Journal Title: Nat Communications Volume: 7 Issue: 1 Pages: 10594-10594
  • DOI: 10.1038/ncomms10594
  • NAID: 120006535052
  • URL: https://pure.teikyo.jp/en/publications/6d10cbbf-3e7f-4e5b-bfce-ab50e6dde489
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder. (2015)
  • Author(s): Hashimoto R, Nakazawa T, Tsurusaki Y, Yasuda Y, Nagayasu K, Matsumura K, Kawashima H, Yamamori H, Fujimoto M, Ohi K, Umeda-Yano S, Fukunaga M, Fujino H, Kasai A, Hayata-Takano A, Shintani N, Takeda M, Matsumoto N, Hashimoto H.
  • Journal Title: Journal of Human Genetics Volume: 61 Issue: 3 Pages: 199-206
  • DOI: 10.1038/jhg.2015.141
  • Peer Reviewed / Open Access
• [Presentation] CNS創薬を支援する疾患モデルの開発 (2017)
  • Author(s): 橋本均、笠井淳司、中澤敬信
  • Organizer: 日本安全製薬理研究会 第8回学術年会
  • Place of Presentation: 東京都文京区 東京大学講堂
  • Year and Date: 2017-02-10
  • Invited
• [Presentation] ASD-associated de novo mutations in POGZ impair the DNA-binding activity of POGZ (2016)
  • Author(s): Nakazawa T, Matsumura K, Nagayasu K, Kasai A, Hayata-Takano A, Shintani N, Takuma K, Yamamori H, Yasuda Y, Hashimoto R, Hashimoto H
  • Organizer: 55th Annual Meeting, ACNP
  • Place of Presentation: Diplomat Resort & Spa, Hollywood, Florida, Hollywood FL USA
  • Year and Date: 2016-12-04
  • Int'l Joint Research
• [Presentation] iPS細胞を用いたクロザピン反応性のメチル化解析 (2016)
  • Author(s): 沼田周助、菊地正隆、中澤敬信、橋本亮太
  • Organizer: 第26回 日本臨床精神神経薬理学会
  • Place of Presentation: 大分県大分市 ホルトホール大分
  • Year and Date: 2016-11-17
  • Invited
• [Presentation] iPS細胞関連技術を用いた統合失調症患者のクロザピン応答性の個人間の相違の分子機構解析 (2016)
  • Author(s): 中澤敬信、橋本亮太、橋本均
  • Organizer: 第46回 日本神経精神薬理学会年会
  • Place of Presentation: 韓国ソウル市 COEX
  • Year and Date: 2016-07-02
  • Invited
• [Presentation] iPS細胞関連技術を用いたクロザピン応答性の分子基盤解析 (2016)
  • Author(s): 藤原幹也、菊地正隆、永安一樹、中澤敬信、山森英長、笠井淳司、早田敦子、新谷紀人、藤本美智子、
  • Organizer: 第89回 日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-09
• [Presentation] 統合失調症関連遺伝子のマウス脳における発現解析 (2016)
  • Author(s): 岩田晋平、松村憲佑、永安一樹、馬場優志、笠井淳司、早田敦子、新谷紀人、田熊一敞、中澤敬信、 橋本均
  • Organizer: 第130回日本薬理学会近畿部会
  • Place of Presentation: 京都府京都市 京都大学講堂
• [Presentation] 自閉症の疾患特異的候補遺伝子の機能的スクリーニング (2015)
  • Author(s): 松村憲佑、橋本亮太、中澤敬信、鶴崎美徳、安田由華、永安一樹、川島和、山森英長、藤本美智子、
  • Organizer: 第38回日本神経科学会大会
  • Place of Presentation: 神戸国際会議場 (兵庫県神戸市）
  • Year and Date: 2015-07-28
• [Remarks] 大阪大学大学院薬学研究科神経薬理学分野
  • URL: http://molpharm.umin.jp/
• [Remarks] 大阪大学大学院歯学研究科薬理学教室
  • URL: http://web.dent.osaka-u.ac.jp/~pharm/