Analysis of mTOR signaling in central nervous systems

• Project/Area Number: 15K06701
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurophysiology / General neuroscience
• Research Institution: The University of Tokyo
• Principal Investigator: Kassai Hidetoshi 東京大学, 大学院医学系研究科(医学部), 准教授 (40403232)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: mTOR / トランスジェニックマウス / 小脳 / 遺伝子操作マウス / 小脳プルキンエ細胞 / マウス

Outline of Final Research Achievements

We aimed to examine mTOR functions in cerebellar Purkinje cells (PCs) by establishing a mouse model of chronically activated mTOR pathway in PCs. Using constitutively active mTOR, we established double transgenic mice line, in which active mTOR mutant is expressed specifically in PCs (L7-mTOR Tg mice). Immunohistochemical analysis showed that PCs of L7-mTOR Tg mice were remarkably hypertrophied and significantly decreased in their number at 4 weeks of age. Molecularly, L7-mTOR Tg PCs were immunopositive for cleaved caspase 3 and HIF-1alpha, suggesting that PC loss by mTORC1 activation may be caused by apoptotic cell death via hypoxic stress signaling. Behavioral analyses revealed that L7-mTOR Tg mice displayed impaired motor coordination, but normal social behavior. Together, these results indicate that mTORC1 signaling is essential for PC survival and cerebellar functions.

Research Products

• [Journal Article] Apolipoprotein M Protects Lipopolysaccharide-Treated Mice from Death and Organ Injury. (2018)
  • Author(s): Kurano M, Tsuneyama K, Morimoto Y, Shimizu T, Jona M, Kassai H, Nakao K, Aiba A, Yatomi Y
  • Journal Title: Thromb Haemost. Volume: 印刷中 Issue: 06 Pages: 1021-1035
  • DOI: 10.1055/s-0038-1641750
  • Peer Reviewed
• [Journal Article] Oocyte-activating capacity of fresh and frozen-thawed spermatids in the common marmoset (Callithrix jacchus). (2018)
  • Author(s): Ogonuki N, Inoue H, Matoba S, Kurotaki YK, Kassai H, Abe Y, Sasaki E, Aiba A, Ogura A
  • Journal Title: Mol Reprod Dev Volume: - Issue: 5 Pages: 376-386
  • DOI: 10.1002/mrd.22971
  • Peer Reviewed / Open Access
• [Journal Article] Use of human methylation arrays for epigenome research in the common marmoset (Callithrix jacchus). (2017)
  • Author(s): Ueda J, Murata Y, Bundo M, Oh-Nishi A, Kassai H, Ikegame T, Zhao Z, Jinde S, Aiba A, Suhara T, Kasai K, Kato T, Iwamoto K
  • Journal Title: Neuroscience Research Volume: in press Pages: 60-65
  • DOI: 10.1016/j.neures.2017.02.005
  • Peer Reviewed
• [Journal Article] Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways. (2016)
  • Author(s): Kikuchi I, Takahashi-Kanemitsu A, Sakiyama N, Tang C, Tang PJ, Noda S, Nakao K, Kassai H, Sato T, Aiba A, and Hatakeyama M.
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 12887-12887
  • DOI: 10.1038/ncomms12887
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] mTORの活性化変異と疾患発生 (2016)
  • Author(s): 葛西秀俊、饗場篤、前田達哉
  • Journal Title: 結節性硬化症の診断と治療最前線 Volume: - Pages: 46-51
• [Journal Article] Rho GTPase protein Cdc42 is critical for postnatal cartilage development. (2016)
  • Author(s): Nagahama R, Yamada A, Tanaka J, Aizawa R, Suzuki D, Kassai H, Yamamoto M, Mishima K, Aiba A, Maki K, Kamijo R.
  • Journal Title: Biochem Biophys Res Commun Volume: 470 Issue: 4 Pages: 813-817
  • DOI: 10.1016/j.bbrc.2016.01.111
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Activation of mTORC1 signaling in cerebellar Purkinje cells causes cell death and hypertrophy of Purkinje cells (2017)
  • Author(s): 坂井祐介・葛西秀俊・中山寿子・中尾和貴・前田達哉・橋本浩一・狩野方伸・饗場篤
  • Organizer: 第40回 日本神経科学大会
• [Presentation] Activation of mTORC1 signaling in cerebellar Purkinje cells causes cell death and hypertrophy of Purkinje cells (2017)
  • Author(s): 坂井祐介・葛西秀俊・中山寿子・中尾和貴・前田達哉・橋本浩一・狩野方伸・饗場篤
  • Organizer: 第40回 日本分子生物学会年会
• [Presentation] Genetic manipulation of mTORC1 signaling in mouse cerebellar Purkinje cell (2016)
  • Author(s): Hidetoshi Kassai, Yusuke Sakai, Hisako Nakayama, Tatsuya Maeda, Kouichi Hashimoto, Masanobu Kano, Atsu Aiba
  • Organizer: 46th annual meeting of the Society for Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Book] 動物/疾患モデルの作製技術・病態解析・評価手法、恒常的活性化型mTOR による精神神経疾患モデルマウスの作製 (2017)
  • Author(s): 葛西秀俊・坂井祐介・饗場篤
  • Total Pages: 428
  • Publisher: 技術情報協会
  • ISBN: 9784861046650
• [Remarks] 東京大学大学院医学系研究科・疾患生命工学センター・動物資源学部門
  • URL: http://lar.cdbim.m.u-tokyo.ac.jp/index.html