Identification and analysis of novel mTOR-interacting protein

• Project/Area Number: 18K06478
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• 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): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: mTOR / Flightless-I / knockout mice / Flii / 遺伝子操作マウス / 行動解析 / 脳神経

Outline of Final Research Achievements

In this study, I analyzed mTOR protein complex extracted from the mouse cerebral cortex by mass spectrometry, and identified the novel mTOR-interacting protein, Flightless-I (Flii). Flii is known as the cytoskeleton-regulating protein, but little is known about its function in the central nervous system.
We generated dorsal telencephalon-specific Flii conditional knockout mice (Flii cKO) by CRISPR/Cas9 system. The histological analysis revealed the atrophy of the cerebral cortex in Flii cKO mice, probably due to the apoptotic cell death of cortical progenitor cells during embryonic period. These phenotypes were also observed in the transgenic mice expressing active mTOR in the dorsal telencephalon. Therefore, Flii involved in the brain development, and may have relationship with the mTOR signaling.

Academic Significance and Societal Importance of the Research Achievements

mTORシグナルは、がんや結節性硬化症、自閉症、神経編疾患など、ヒトの多様な疾患に深く関与していることが知られており、その発症メカニズムや治療法が深く研究されている分野である。本研究では大脳皮質における新規のmTOR 相互作用因子として同定されたFliiの機機能解析を遺伝子改変マウスを用いて行った。Fliiノックアウトマウスの表現型は、mTORシグナルが過剰に活性化したマウスと類似している。このことから、学術的にはこれまで十分明らかではなかった神経系におけるmTORシグナルの機能に迫ることができ、社会的にはヒトの疾患のメカニズムの解明や治療戦略に寄与できると考えられる。

Research Products

• [Journal Article] 14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice (2021)
  • Author(s): Norihiko Yokoi, Yuko Fukata, Kei Okatsu, Atsushi Yamagata, Yan Liu , Makoto Sanbo, Yuri Miyazaki, Teppei Goto, Manabu Abe , Hidetoshi Kassai, Kenji Sakimura, Dies Meijer, Masumi Hirabayashi, Shuya Fukai, Masaki Fukata
  • Journal Title: Cell Reports Volume: 37 Issue: 11 Pages: 110107-110107
  • DOI: 10.1016/j.celrep.2021.110107
  • NAID: 120007177780
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Telencephalon-specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning (2021)
  • Author(s): Layla Kawarada, Masahiro Fukaya, Ryo Saito, Hidetoshi Kassai, Hiroyuki Sakagami, Atsu Aiba
  • Journal Title: FEBS Letters Volume: 595 Issue: 12 Pages: 1671-1680
  • DOI: 10.1002/1873-3468.14098
  • Peer Reviewed
• [Journal Article] Identification of GLUT12/SLC2A12 as a urate transporter that regulates the blood urate level in hyperuricemia model mice. (2020)
  • Author(s): Toyoda Y, Takada T, Miyata H, Matsuo H, Kassai H, Nakao K, Nakatochi M, Kawamura Y, Shimizu S, Shinomiya N, Ichida K, Hosoyamada M, Aiba A, Suzuki H
  • Journal Title: Proc. Natl.Acad. Sci. USA Volume: 117 Issue: 31 Pages: 18175-18177
  • DOI: 10.1073/pnas.2006958117
  • Peer Reviewed / Open Access
• [Journal Article] Protection Against Insulin Resistance by Apolipoprotein M/Sphingosine-1-Phosphate. (2020)
  • Author(s): Kurano M, Tsukamoto K, Shimizu T, Kassai H, Nakao K, Aiba A, Hara M, Yatomi Y.
  • Journal Title: Diabetes Volume: 69 Issue: 5 Pages: 867-881
  • DOI: 10.2337/db19-0811
  • NAID: 40022523253
  • Peer Reviewed
• [Journal Article] Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells. (2019)
  • Author(s): Sakai Y, Kassai H, Nakayama H, Fukaya M, Maeda T, Nakao K, Hashimoto K, Sakagami H, Kano M, Aiba A.
  • Journal Title: Scientific Reports Volume: Feb 26;9(1) Issue: 1 Pages: 2799-2799
  • DOI: 10.1038/s41598-019-38730-4
  • Peer Reviewed / Open Access
• [Journal Article] New Features on the Expression and Trafficking of mGluR1 Splice Variants Exposed by Two Novel Mutant Mouse Lines. (2018)
  • Author(s): Rika Naito, Hidetoshi Kassai, Yusuke Sakai, Sabine Schönherr, Masahiro Fukaya, Christoph Schwarzer, Hiroyuki Sakagami, Kazuki Nakao, Atsu Aiba, Francesco Ferraguti
  • Journal Title: Frontiers in Molecular Neuroscience Volume: 11 Pages: 439-439
  • DOI: 10.3389/fnmol.2018.00439
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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