Expression and functional analysis of the imprinting genes located in 15q11-13

• Project/Area Number: 16K19066
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Tamada Kota 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (10550957)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ゲノムインプリンティング / 自閉症 / 遺伝子発現 / Ndn / 15q11-q13 / Prader-Willi syndrome / Genome Imprinting / CRISPR/Cas9 / 15q11-13 / CRISPR / PWS

Outline of Final Research Achievements

The cytogenetic aberration of human chromosome 15q11-q13 causes neurodevelopmental disorders including autism, Prader-Willi (PWS) and Angelman syndrome (AS). Duplication of this region, called 15q11-13 duplication syndrome, is the most frequently found in cytogenetic abnormality in autism. Thus, precise expression of the genes in this region is critical for normal brain development. Previously, we modeled this chromosome duplication in mice and found paternally inherited duplication (patDp/+) causes abnormal social behaviors and serotonin imbalance.
In this study, we identified Ndn genes is critical not only for autistic like behaviors but synaptic development or cortical excitatory/inhibitory balance.

Academic Significance and Societal Importance of the Research Achievements

ヒト染色体15q11-13領域ではこれまでUbe3aという遺伝子のみが着目されてきた。しかし、近年になりUbe3aを含まない重複自閉症者が認められてきたことから、Ube3a以外の遺伝子も関与する可能性が挙げられてきた。しかし、その原因はこれまで明らかになっていない。本研究結果はNdnが新たな15q11-13領域中でのリスクとなり、自閉症発症分子メカニズム解明に向けた一歩となりうることを証明した成果となる。

Research Products

• [Journal Article] UBE3A regulates the transcription of IRF, an anti-viral immunity (2019)
  • Author(s): Furumai R, Tamada K, Liu X, Takumi T
  • Journal Title: Hum Mol Genet Volume: in press Issue: 12 Pages: 1947-1958
  • DOI: 10.1093/hmg/ddz019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of genes regulating GABAergic interneuron maturation. (2018)
  • Author(s): Fukumoto K, Tamada K, Toya T, Nishino T, Yanagawa Y, Takumi T
  • Journal Title: Neurosci Res Volume: - Pages: 18-29
  • DOI: 10.1016/j.neures.2017.11.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CNV biology in neurodevelopmental disorders (2018)
  • Author(s): Takumi Toru、Tamada Kota
  • Journal Title: Current Opinion in Neurobiology Volume: 48 Pages: 183-192
  • DOI: 10.1016/j.conb.2017.12.004
  • Peer Reviewed / Open Access
• [Journal Article] Behavioral and neuroanatomical analyses in a genetic mouse model of 2q13 duplication (2017)
  • Author(s): Kishimoto Keiko、Nomura Jun、Ellegood Jacob、Fukumoto Keita、Lerch Jason P.、Moreno-De-Luca Daniel、Bourgeron Thomas、Tamada Kota、Takumi Toru
  • Journal Title: Genes to Cells Volume: 22 Issue: 5 Pages: 436-451
  • DOI: 10.1111/gtc.12487
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice (2017)
  • Author(s): Nakai N, Nagano M, Saitow F, Watanabe Y, Kawamura Y, Kawamoto A, Tamada K, Mizuma H, Onoe H, Watanabe Y, Monai H, Hirase H, Nakatani J, Inagaki H, Kawada T, Miyazaki T, Watanabe M, Sato Y, Okabe S, Kitamura K, Kano M, Hashimoto K, Suzuki H, Takumi T.
  • Journal Title: Sci Adv. Volume: 3 Issue: 6
  • DOI: 10.1126/sciadv.1603001
  • Peer Reviewed / Open Access
• [Journal Article] Functional significance of rare neuroligin 1 variants found in autism (2017)
  • Author(s): Nakanishi Moe、Nomura Jun、Ji Xiao、Tamada Kota、Arai Takashi、Takahashi Eiki、Bu?an Maja、Takumi Toru
  • Journal Title: PLOS Genetics Volume: 13 Issue: 8 Pages: e1006940-e1006940
  • DOI: 10.1371/journal.pgen.1006940
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] In vivo screening of maternally imprinted genes in human chromosome 15q11-q13 (2019)
  • Author(s): Kota Tamada, Keita Fukumoto, Tsuyoshi Toya, Nobuhiro Nakai, Janak Awasthi, Sandra Ruf, Francois Spitz, Tomokazu Tsurugizawa, Toru Takumi
  • Organizer: RIKEN EPIGENETICS in Wako
  • Int'l Joint Research
• [Presentation] 自閉症責任領域15q11-q13モデルマウスにおける 原因遺伝子の探索 (2018)
  • Author(s): 玉田 紘太、福本 景太、戸谷 豪志、中井 信裕、Ruf Sandra, Spitz Francois, 内匠 透
  • Organizer: 次世代脳
• [Presentation] 自閉症責任領域15q11-q13モデルマウスにおける原因遺伝子の探索 (2017)
  • Author(s): 玉田紘太、福本景太、戸谷豪志、Ruf Sandra、Spitz Francois、内匠 透
  • Organizer: ConBio2017
  • Int'l Joint Research