ENU変異マウスを用いた行動異常発症に関わる遺伝子の機能解析

• Project/Area Number: 20016013
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Fujita Health University (2009); Kyoto University (2008)
• Principal Investigator: 宮川 剛 Fujita Health University, 総合医科学研究所, 教授 (10301780)
• Co-Investigator(Kenkyū-buntansha): 高雄 啓三 京都大学, 医学研究科, 講師 (80420397)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥8,600,000 (Direct Cost: ¥8,600,000); Fiscal Year 2009: ¥4,300,000 (Direct Cost: ¥4,300,000); Fiscal Year 2008: ¥4,300,000 (Direct Cost: ¥4,300,000)
• Keywords: gene-drivenミュータジェネシス / ENU変異マウス / 網羅的行動テスト / 統合失調症 / 精神疾患 / 遺伝子改変マウス / 脳・神経 / 行動テストバッテリー / 遺伝子 / 行動学 / ゲノム

Research Abstract

αCaMKIIヘテロノックアウトマウスは、精神疾患様の顕著な行動異常を示し、脳の海馬歯状回の神経細胞が未成熟なままであることが研究代表者からの研究で明らかになっている。本年度は、理研で開発されたENU変異マウスを活用することにより、どのような遺伝子のどのような変異が精神疾患様の行動異常及び未成熟歯状回という中間表現型に重要な役割をはたすのか検討することを目的として以下の研究を進めた。
1. カルシニューリン関連遺伝子のうちCaMKIIB、Dynamin遺伝子については、理研のgene-driven法のスクリーニングによりアミノ酸置換変異が3種類(系統)見いだされた。現在、これらは遺伝子機能の面と一次スクリーニングの結果を検討中で、今後、優先度の高いものから入手して繁殖を進める。
2. 理研のphenotype-driven法による一次スクリーニングにおいて、顕著な行動異常があるとされたM100073, M100786, M100914, M100934の4系統については、精子stockを入手して人工受精・胚移植技術を用いて個体に戻し、行動実験用マウスを準備する繁殖を進め、3月末までに4系統あわせて100匹程度の行動実験用マウスを得た。
3. ヒトの精神疾患感受性遺伝子として注目されるDISC1遺伝子については、鬱病モデルQ31L変異マウス、統合失調症モデルL100P変異マウスなど3系統を入手した。Q31L, L100Pマウスについては交配用ヘテロマウスの繁殖を進め、もう1系統は戻し交配を進めている。
以上のマウスの繁殖は、ピーク時期が重ならないように自然交配と人工受精・胚移植の方法を組み合わせて計画的にマウスを増やしており、必要数の成体マウスが得られ次第、順次、網羅的行動解析と未成熟歯状回の検討を行う。

Research Products

• [Journal Article] Mice with altered myelin proteolipid protein gene expression display cognitive deficits accompanied by abnormal neuron-glia interactiohs and decreased conduction velocities (2010)
  • Author(s): Tanaka et al.
  • Journal Title: Journal of Neuroscience 26 Pages: 8363-71
  • Peer Reviewed
• [Journal Article] Comprehensive behavioral analysis of calcium/calmodulin-dependent protein kinase IV knockout mice (2010)
  • Author(s): Takao et al.
  • Journal Title: PLoS ONE 5(3)
  • Peer Reviewed
• [Journal Article] SDOP-DB : A comparative standardised-protocol database for mouse phenotypic analyses (2010)
  • Author(s): Tamaka et al.
  • Journal Title: Bioinformatics 15 Pages: 1133-4
  • Peer Reviewed
• [Journal Article] Abnormal behavior in a chromosome- engineered mouse model for human 15q11-13 duplication seen in autism (2009)
  • Author(s): Nakatani J et al.
  • Journal Title: Cell 137 Pages: 1235-46
  • Peer Reviewed
• [Journal Article] Comprehensive behavioral phenotyping of ryanodine receptor type 3(RyR3)knockout mice : decreased social contact duration in two social interaction tests (2009)
  • Author(s): Matsuo N et al.
  • Journal Title: Frontiers in Behavioral Neuroscience 3
  • Peer Reviewed
• [Journal Article] Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice (2009)
  • Author(s): Tanda et al.
  • Journal Title: Molecular Brain 2 Pages: 19-19
  • Peer Reviewed
• [Journal Article] Neural activity changes underlying the working memory deficit in alpha-CaMKII heterozygous knockout mice (2009)
  • Author(s): Matsuo et al.
  • Journal Title: Frontiers in Behavioral Neuroscience 3 Pages: 20-20
  • Peer Reviewed
• [Journal Article] Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly (2009)
  • Author(s): Yamada et al.
  • Journal Title: Nature Medicine 15(10) Pages: 1202-7
  • Peer Reviewed
• [Journal Article] Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system (2009)
  • Author(s): Ohno et al.
  • Journal Title: Nature Neuroscience 12 Pages: 1506-13
  • Peer Reviewed
• [Journal Article] Abnormalities in brain structure and behavior in GSK-3α mutant mice (2009)
  • Author(s): Kaidanovich-Beilin et al.
  • Journal Title: Molecular Brain 2(1) Pages: 35-35
  • Peer Reviewed
• [Journal Article] Dissection of hippocampal dentate gyrus from adult mice (2009)
  • Author(s): Hagihara et al.
  • Journal Title: Journal of Visualized Experiments 33
  • Peer Reviewed
• [Journal Article] Ischemia-induced neurogenesis of neocortical layer 1 progenitor cells (2009)
  • Author(s): Ohira et al.
  • Journal Title: Nature Neuroscience 13(2) Pages: 173-9
  • Peer Reviewed
• [Journal Article] Smaller dendritic spines, weaker synaptic transmission butenhanced spatial learning in mice lacking shank1 (2008)
  • Author(s): Hung, AY., Futai, K., Sala, C., Valtschanoff, JG., Ryu, J., Burgoon, M., Kidd, FL., Sung, CC., Miyakawa, T., Bear, MF., Weinberg, RJ., and Shene. M
  • Journal Title: Journal of Neuroscience 28(7) Pages: 1697-1708
  • Peer Reviewed
• [Journal Article] Increased social interaction in mice deficient of the striatal medium spiny neuron-specific phosphodiesterase 10A2 (2008)
  • Author(s): Sano, H., Nagai, Y., Miyakawa, T., Shigemoto, R., Yokoi, M
  • Journal Title: Journal of Neurochemistry 105 Pages: 546-556
  • Peer Reviewed
• [Journal Article] Increased anxiety-like behavior in neuropsin(kallikrein-related peptidase 8)gene-deficient mice (2008)
  • Author(s): Horii, Y., Yamasaki, N. , Miyakawa, T., and Shiosaka, S
  • Journal Title: Behavioral Neuroscience 122(3) Pages: 498-504
  • Peer Reviewed
• [Journal Article] Down-regulation of protocadherin-_, A isoforms in mice changescontextual fear conditioning and spatial working memory (2008)
  • Author(s): Fukuda, E., Hamada, S., Hasegawa, S., Katori, S., Sanbo, M., Miyakawa, T., Yamamoto, T., Yamamoto, H., Hirabayashi, T., Yagi, T
  • Journal Title: European Journal of Neuroscience 28(7) Pages: 1362-76
  • Peer Reviewed
• [Journal Article] Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants (2008)
  • Author(s): Sakae, N. , Yamasaki, N., Kitaichi, K., Fukuda, T, Yamada, M., Yoshikawa, H., Hiranita, T., Tatsumi, Y., Kira, J., Yamamoto, T., Miyakawa, T., Nakayama, KI
  • Journal Title: Human Molecular Genetics 17(20) Pages: 3191-203
  • Peer Reviewed
• [Journal Article] Identification of YWHAE, a gene encoding 14-3-3epsilon, as apossible susceptibility gene for schizophrenia (2008)
  • Author(s): Ikeda, M., Hikita, T., Taya, S., Uraguchi-Asaki, J., Toyo-oka, K., Wynshaw-Boris, A., Ujike, H., Inada, T., Takao, K., Miyakawa, T., Ozaki, N., Kaibuchi, K., Iwata, N
  • Journal Title: Human Molecular Genetics 17(20) Pages: 3212-22
  • Peer Reviewed
• [Journal Article] Roles of continuous neurogenesis in the structural andfunctional integrity of the adult forebrain (2008)
  • Author(s): Imayoshi, I., Sakamoto, M., Ohtsuka, T., Takao, K., Miyakawa, T., Yamaguchi, M., Mori, K., Ikeda, T., Itohara, S., Kageyama, R
  • Journal Title: Nature Neuroscience 11(10) Pages: 1153-61
  • Peer Reviewed
• [Journal Article] Mice lacking the kf-1 gene exhibit increased anxiety- but notdespair-like behavior (2008)
  • Author(s): Tsujimura, A., Matsuki, M., Takao, K., Yamanishi, K., Miyakawa, T., and Hashimoto-Gotoh, T
  • Journal Title: Frontiers in Behavioral Neuroscience 2 Pages: 4-4
  • Peer Reviewed
• [Journal Article] Alpha-CaMKII deficiency causes immature dentate gyrus, a novelcandidate endophenotype of psychiatric disorders (2008)
  • Author(s): Yamasaki, N., Maekawa, M., Kobayashi, K., Kajii, Y., Maeda, J., Soma, M., Takao, K., Tanda, K., Ohira, K., Toyama, K., Kanzaki, K., Fukunaga, K., Sudo, Y., Ichinose, H., Ikeda, M., Iwata, N. , Ozaki, N., Suzuki, H., Higuchi, M., Suhara, T., Yuasa, S., Miyakawa, T
  • Journal Title: Molecular Brain 1 Pages: 6-6
  • Peer Reviewed
• [Journal Article] Comprehensive behavioral phenotyping of calpastatin-knockout mice (2008)
  • Author(s): Nakajima, R., Takao, K., Huang, SM., Takano, J., Iwata, N., Miyakawa, T., Saido, TC
  • Journal Title: Molecular Brain 1 Pages: 7-7
  • Peer Reviewed
• [Journal Article] Impaired long-term memory retention and working memory in sdymutant mice with a deletion in Dtnbp1, a susceptibility genefor schizophrenia (2008)
  • Author(s): Takao, K., Toyama, K., Nakanishi, K., Hattori, S., Takamura, H., Takeda, M., Miyakawa, T., and Hashimoto, R
  • Journal Title: Molecular Brain 1 Pages: 11-11
  • Peer Reviewed
• [Journal Article] Normal mitochondrial respiratory function is essential forspatial remote memory in mice (2008)
  • Author(s): Tanaka, D., Nakada, K., Takao, K., Ogasawara, E., Kasahara, A., Sato, A., onekawa, H., Miyakawa, T., Hayashi, J
  • Journal Title: Molecular Brain 1 Pages: 21-21
  • Peer Reviewed
• [Presentation] Omics analysis of immature dentate gyrus : Possible mechanisms underlying maturation failure of granule cells (2009)
  • Author(s): 宮川剛
  • Organizer: 4^<th> International Conference of Neurons and Brain Disease
  • Place of Presentation: トロント、カナダ
• [Presentation] Deletion of Schnurri-2 causes abnormal behaviors related to psychiatric disorders and failure in the maturation of the dentate granule cells in mice (2009)
  • Author(s): Takao, K., Kobayashi, K., Hagihara, H., Ohira, K., Yamasaki, N., Komada, M., Toyama, K., Takagi, T., Ishii, S., Miyakawa, T.
  • Organizer: 第36回国際生理学会世界大会
  • Place of Presentation: 京都
• [Presentation] 精神疾患の中間表現型としての未成熟歯状回 (2009)
  • Author(s): 宮川剛
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] alpha-CaMKIIヘテロ欠損マウスとShn2欠損マウスの海馬のプロテオミクス解析 (2009)
  • Author(s): 萩原英雄、高雄啓三、遠山桂子、中村政志、高崎昭彦、橋本敬一郎、林宣宏、宮川剛
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] α-CaMKIIヘテロ欠損マウスの海馬遺伝子発現パターン解析 (2009)
  • Author(s): 高雄啓三、宮川剛
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] カルシニューリン抑制因子Zaki-4 Tgマウスの行動解析 (2009)
  • Author(s): 遠山桂子、山崎信幸、高雄啓三、宮川剛
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice (2009)
  • Author(s): Takao, K., Tanda, K., Matsuo, N., Nakanishi, K., Toyama, K., Yamasaki, N., Sugimoto, T., Nishi, A., Miyakawa, T.
  • Organizer: Neuroscience 2009
  • Place of Presentation: シカゴ、アメリカ
• [Presentation] 精神疾患の中間表現型としての未成熟歯状回 (2009)
  • Author(s): 宮川剛
  • Organizer: 第19回日本臨床精神神経薬理学会・第39回日本神経精神薬理学会 合同年会
  • Place of Presentation: 京都
• [Presentation] 精神疾患の中間表現型としての未成熟歯状回 (2009)
  • Author(s): 宮川剛
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜