Exploration of physiological functions of mammalian septins with genetically engineered mouse lines

• Project/Area Number: 23370084
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cell biology
• Research Institution: Nagoya University
• Principal Investigator: KINOSHITA Makoto 名古屋大学, 理学(系)研究科(研究院), 教授 (30273460)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000); Fiscal Year 2013: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2012: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
• Keywords: セプチン / アクチン / 微小管 / 細胞骨格 / 細胞表層 / アセチル化 / 神経突起 / シナプス伝達 / 神経 / 行動 / 脱アセチル化 / 大脳皮質ニューロン / 神経回路形成 / 遺伝子改変マウス / RNA干渉 / 蛍光イメージング / 電子顕微鏡 / マウス

Research Abstract

Septins are evolutionarily conserved polymerizing GTPases like the major cytoskeletal nucleotide-binding proteins of tubulins and actins, however, their physiological functions in metazoans are largely unknown. To address this: 1) We have established a line of conditional SEPT7 knockout mice and uncovered that septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation. 2) We established prion-promoter-driven SEPT4 transgenic mice and uncovered that chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. These and other findings, in addition to mouse lines and a set of reagents created in this study, will help understand cellular/molecular mechanisms of septin functions in relation to other cytoskeletal systems in physiologically relevant contexts.

Research Products

• [Journal Article] Phosphatidic acid-preferring phospholipase A1 regulates mitochondrial dynamics. (2014)
  • Author(s): Baba T, Kashiwagi Y, Arimitsu N, Kogure T, Edo A, Maruyama T, Nakao K, Nakanishi H, Kinoshita M, Frohman MA, Yamamoto A, Tani K.
  • Journal Title: Journal of Biological Chemistry Volume: 289 Issue: 16 Pages: 11497-11511
  • DOI: 10.1074/jbc.m113.531921
  • Peer Reviewed / Open Access
• [Journal Article] Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice (2013)
  • Author(s): Ageta-Ishihara N, Yamakado H, Morita T, Hattori S, Takao K, Miyakawa T, Takahashi R, Kinoshita M
  • Journal Title: Molecular Brain Volume: 6 Pages: 35-35
  • URL: http://www.molecularbrain.com/content/6/1/35
• [Journal Article] Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation (2013)
  • Author(s): Ageta-Ishihara N, Miyata T, Ohshima C, Watanabe M, Sato Y, Hamamura Y, Higashiyama T, Mazitschek R, Bito H, Kinoshita M
  • Journal Title: Nature Communications Volume: 4 Pages: 2532-2532
  • URL: http://www.nature.com/ncomms/2013/131011/ncomms3532/full/ncomms3532.html
• [Journal Article] Septins promote dendrite and axon development by negatively regulating microtubule stability viaHDAC6-mediated deacetylation. (2013)
  • Author(s): Ageta-Ishihara N, Miyata T, Ohshima O, Watanabe M, Sato Y, Hamamura Y, Higashiyama T, Mazitschek R, Bito H, Kinoshita M.
  • Journal Title: Nat Commun Volume: 4 Issue: 1 Pages: 2532-2532
  • DOI: 10.1038/ncomms3532
  • Peer Reviewed
• [Journal Article] Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice (2013)
  • Author(s): Ageta-Ishihara N, Yamakado H, Morita T, Hattori S, Takao K, Miyakawa T, Takahashi R, Kinoshita M
  • Journal Title: Mol Brain Volume: 6 Issue: 1 Pages: 35-35
  • DOI: 10.1186/1756-6606-6-35
  • Peer Reviewed / Open Access
• [Journal Article] 運動による脳の活性化のしくみ (2013)
  • Author(s): 上田（石原）奈津実、木下 専
  • Journal Title: 健康医科学 Volume: 28 Pages: 44-51
  • Peer Reviewed
• [Journal Article] Ito J. Localization of septin proteins in the mouse cochlea (2012)
  • Author(s): Yoshida A, Yamamoto N, Kinoshita M, Hiroi N, Hiramoto T, Kang G, Trimble WS, Tanigaki K, Nakagawa T
  • Journal Title: Hearing Research Volume: 289 Pages: 40-51
  • URL: http://www.sciencedirect.com/science/article/pii/S0378595512001013
• [Journal Article] Hear Res Localization of septin proteins in the mouse cochlea (2012)
  • Author(s): Yoshida A, Yamamoto N, Kinoshita M, Hiroi N, Hiramoto T, Kang G, Trimble WS, Tanigaki K, Nakagawa T, Ito J.
  • Journal Title: Epub ahead of print Volume: 289 Issue: 1-2 Pages: 40-51
  • DOI: 10.1016/j.heares.2012.04.015
  • Peer Reviewed
• [Journal Article] Localization of septin proteins in the mouse cochlea (2012)
  • Author(s): Yoshida A, Yamamoto N, Kinoshita M, Hiroi N, Hiramoto T, Kang G, Trimble WS, Tanigaki K, Nakagawa T, Ito J
  • Journal Title: Hearing Research Volume: (in press)(未定)
  • Peer Reviewed
• [Journal Article] Submembranous septins as relatively stable components of actin-based membrane skeleton (2011)
  • Author(s): A.Hagiwara, Y.Tanaka, R.Hikawa, N.Morone, A.Kusumi, H.Kimura, M.Kinoshita
  • Journal Title: Cytoskeleton Volume: 68 Issue: 9 Pages: 512-525
  • DOI: 10.1002/cm.20528
  • Peer Reviewed
• [Journal Article] Downregulation of the Wnt antagonist Dkk2 links the loss of Sept4 and myofibroblastic transformation of hepatic stellate cells (2011)
  • Author(s): Yanagida A, Iwaisako K, Hatano E, Taura K, Sato F, Narita M, Nagata H, Asechi H, Uemoto S, Kinoshita M
  • Journal Title: BBA-Molecular Basis of Disease Volume: 812 Pages: 1403-1411
  • NAID: 120003517932
  • URL: http://www.sciencedirect.com/science/article/pii/S0925443911001414
• [Presentation] 遺伝子改変マウスの認知/行動異常から見えてきた脳内セプチン系の多彩な機能 (2014)
  • Author(s): 木下 専
  • Organizer: 京都大学分子生体統御学セミナー
  • Year and Date: 2014-03-31
• [Presentation] 生理学研究所共同研究制度を活用したセプチンおよび関連遺伝子欠損マウスの行動解析 (2014)
  • Author(s): 木下 専
  • Organizer: 生理学研究所 行動・代謝分子解析センター行動様式解析室 研究会
  • Year and Date: 2014-02-24
• [Presentation] Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation (2013)
  • Author(s): Ageta-Ishihara N, Miyata T, Ohshima C, Watanabe M, Sato Y, Hamamura Y, Higashiyama T, Mazitschek R, Bito H, Kinoshita M
  • Organizer: 50th ASCB Annual Meeting
  • Year and Date: 2013-12-14
• [Presentation] セプチン細胞骨格の破綻を伴う精神・神経疾患病態モデルの作製と解析 (2013)
  • Author(s): 木下 専
  • Organizer: 第11回神経科学研究会
  • Year and Date: 2013-11-02
• [Presentation] Differential clustering of septin subunits beneath specific perisynaptic membrane domains in the cerebellar cortical neurons and glia (2013)
  • Author(s): Kurita H, Fukazawa Y, Ageta-Ishihara N, Shigemoto R, Kinoshita M
  • Organizer: The 6th international neural microcircuit conference
  • Year and Date: 2013-06-25
• [Presentation] Immuno-EM 3D reconstruction analysis of the septin family GTPases which constitute the membrane skeleton in neurons and glia (2013)
  • Author(s): Kurita H, Fukazawa Y, Ageta-Ishihara N, Shigemoto R, Kinoshita M
  • Organizer: The 14th International Membrane Research Forum
  • Year and Date: 2013-05-15
• [Presentation] Immuno-EM 3D reconstruction analysis of septin subunits in the cerebellum (2013)
  • Author(s): Kurita H, Fukazawa Y, Ageta-Ishihara N, Shigemoto R, Kinoshita M
  • Organizer: Frontiers in Structural Physiology Symposium
  • Year and Date: 2013-01-22
• [Presentation] Impaired cerebellar ultrastructure and motor coordination in mice that lack a septin-interacting protein BORG4/CDC42EP4. (2013)
  • Author(s): Kinoshita M.
  • Organizer: The 50th American Society for Cell Biology Annual Meeting, Special Interest Subgroup Meeting “Septins: Membrane organization and cytoskeletal dynamics from bud necks to dendritic spines.”
  • Place of Presentation: New Orleans, USA
  • Invited
• [Presentation] Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation. (2013)
  • Author(s): Ageta-Ishihara N, Miyata T, Ohshima C, Watanabe M, Sato Y, Hamamura Y, Higashiyama T, Mazitschek R, Bito H, Kinoshita M.
  • Organizer: The 50th ASCB Annual Meeting
  • Place of Presentation: New Orleans, USA
• [Presentation] Differential clustering of septin subunits beneath specific perisynaptic membrane domains in the cerebellar cortical neurons and glia. (2013)
  • Author(s): Kurita H, Fukazawa Y, Ageta-Ishihara N, Shigemoto R, Kinoshita M.
  • Organizer: The 6th international neural microcircuit conference
  • Place of Presentation: Okazaki, Japan
• [Presentation] Immuno-EM 3D reconstruction analysis of septin subunits in the cerebellum. (2013)
  • Author(s): Hiroyuki Kurita, Yugo Fukazawa, Natsumi Ageta-Ishihara, Ryuichi Shigemoto, Makoto Kinoshita.
  • Organizer: Frontiers in Structural Physiology Symposium
  • Place of Presentation: 名古屋大学（愛知県）
• [Presentation] Immuno-EM 3D reconstruction analysis of the septin family GTPases which constitute the membrane skeleton in neurons and glia. (2013)
  • Author(s): Hiroyuki Kurita, Yugo Fukazawa, Natsumi Ageta-Ishihara, Ryuichi Shigemoto, and Makoto Kinoshita.
  • Organizer: The 14th International Membrane Research Forum
  • Place of Presentation: 京都大学（京都府）
• [Presentation] Differential clustering of septin subunits beneath specific perisynaptic membrane domains in the cerebellar cortical neurons and glia. (2013)
  • Author(s): Hiroyuki Kurita, Yugo Fukazawa, Natsumi Ageta-Ishihara, Ryuichi Shigemoto, Makoto Kinoshita.
  • Organizer: The 6th international neural microcircuit conference.
  • Place of Presentation: 岡崎コンファレンスセンター（愛知県）
• [Presentation] Septins facilitate neurite outgrowth through HDAC6-mediated microtubule deacetylation (2012)
  • Author(s): 石原奈津実, 木下 専
  • Organizer: 第35回日本分子生物学会年会
  • Year and Date: 2012-12-12
• [Presentation] 遺伝性 ALSモデルにおける SIRT1 の関与 (2012)
  • Author(s): 永津真司, 築地仁美, 木下 専, 三澤日出巳, 山中宏二
  • Organizer: 日本生化学会年会
  • Year and Date: 2012-12-05
• [Presentation] Septin-dependent microtubule regulation required for the outgrowth of axons and dendrites (2012)
  • Author(s): 石原奈津実, 木下 専
  • Organizer: 第35回日本神経科学大会 公開シンポジウム「神経突起の形成とリモデリングを制御する新規メカニズムと普遍原理」
  • Year and Date: 2012-09-21
• [Presentation] 包括脳支援制度を活用した CDC42-CDC42EP-セプチン系の神経機能の探索 (2012)
  • Author(s): 木下 専
  • Organizer: 生命科学系3分野支援活動(がん,ゲノム,脳)合同シンポジウム-生命科学・医学の発展を支える研究基盤の未来
  • Year and Date: 2012-07-06
• [Presentation] SIRT1 による脳虚血耐性機構に関する検討 (2012)
  • Author(s): 真野 善有, 栗田浩之, 深澤有吾, 上田(石原)奈津実, 重本隆一, 木下 専
  • Organizer: 第53回日本神経学会学術大会
  • Year and Date: 2012-05-22
• [Presentation] Septin-dependent microtubule regulation required for the outgrowth of axons and dendrites (2012)
  • Author(s): Natsumi Ageta-Ishihara, Makoto Kinoshita.
  • Organizer: 第35回日本神経科学大会 公開シンポジウム「神経突起の形成とリモデリングを制御する新規メカニズムと普遍原理」
  • Place of Presentation: 名古屋国際会議場（愛知県）
  • Invited
• [Presentation] Septins facilitate neurite outgrowth through HDAC6-mediated microtubule deacetylation (2012)
  • Author(s): Natsumi Ageta-Ishihara, Makoto Kinoshita.
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場（福岡県）
  • Invited
• [Presentation] Ultrastructural localization analysis of the septin cytoskeleton /scaffold system in mammalian brain (2011)
  • Author(s): Kurita H, Fukazawa Y, Ageta-Ishihara N, Shigemoto R, Kinoshita M
  • Organizer: 生理研研究会「電子顕微鏡機能イメージングの医学・生物学への応用 : 3D イメージングの最先端」
  • Year and Date: 2011-11-30
• [Presentation] 小脳バーグマングリア突起における Cdc42-Cdc42ep4-septin パスウェイの生化学的・機能的解析 (2011)
  • Author(s): Ageta-Ishihara N, Kinoshita M
  • Organizer: 第2回神経科学と構造生物学の融合研究会
  • Year and Date: 2011-11-21
• [Presentation] Septin-dependent microtubule regulation in neurite outgrowth. シンポジウム「ニューロンとグリアにおけるセプチン細胞骨格の機能解明に向けたアプローチ」 (2011)
  • Author(s): Ageta-Ishihara N, Kinoshita M
  • Organizer: 第54回日本神経化学会大会
  • Year and Date: 2011-09-26
• [Presentation] 細胞突起の機能的組織化・区画化を支えるスカフォールド系の生理的意義の解析 (2011)
  • Author(s): 木下 専
  • Organizer: 第84回日本生化学会大会シンポジウム
  • Year and Date: 2011-09-21
• [Presentation] 細胞突起の機能的組織化・区画化を支えるスカフォールド系の生理的意義の解析 (2011)
  • Author(s): 木下専
  • Organizer: 第84回日本生化学会大会シンポジウム
  • Place of Presentation: 京都(招待講演)
  • Year and Date: 2011-09-21
• [Presentation] Ultrastructural localization analysis of the septin cytoskeleton/ scaffold system in mammalian brain (2011)
  • Author(s): Kurita H, Fukazawa Y, Ageta-Ishihara N, Shigemoto R, Kinoshita M
  • Organizer: 第34回日本神経科学大会
  • Year and Date: 2011-09-18
• [Presentation] 遺伝子改変マウスを用いたセプチン細胞骨格系の神経機能と病態へのアプローチ (2011)
  • Author(s): 木下 専
  • Organizer: 文部科学省科研費補助金 新学術領域研究 包括脳ネットワーク 夏のワークショップ
  • Year and Date: 2011-08-23
• [Presentation] ドーパミン神経伝達と変性におけるセプチン細胞骨格の役割 (2011)
  • Author(s): 木下 専
  • Organizer: 第51回脳の医学・生物学研究会
  • Year and Date: 2011-08-06
• [Presentation] Probing physiological roles of septins in neurons and glia (2011)
  • Author(s): Kinoshita M
  • Organizer: Symposium 5 "Cytoskeleton" The 63rd Annual Meeting of the Japanese Society for Cell Biology
  • Place of Presentation: Sapporo, Japan
• [Presentation] Septin-dependent microtubule regulation required for axon and dendrite elongation (2011)
  • Author(s): Ageta-Ishihara N, Kinoshita M
  • Organizer: Society for Neuroscience Annual Meeting
  • Place of Presentation: Washington, D.C
• [Presentation] Probing physiological roles of septins in neurons and glia (2011)
  • Author(s): Kinoshita M
  • Organizer: Symposium 5 The 63rd Annual Meeting of the Japanese Society for CeU Biology
  • Place of Presentation: 札幌(招待講演)
• [Presentation] 小脳バーグマンクリア突起におけるCdc42-Cdc42ep4-septinパスウェイの生化学的・機能的解析 (2011)
  • Author(s): 上田(石原)奈津実、木下専
  • Organizer: 第2回神経科学と構造生物学の融合研究会
  • Place of Presentation: 岡崎(招待講演)
• [Presentation] Septin-dependent microtubule regulation required for axon and dendrite elongation (2011)
  • Author(s): Natsumi Ageta-Ishihara, Makoto Kinoshita
  • Organizer: Society for Neuroscience Annual Meeting
  • Place of Presentation: Washington, D.C.(招待講演)
• [Book] 生化学辞典（第５版） (2013)
  • Author(s): 上田（石原）奈津実、木下 専
  • Publisher: 東京化学同人
• [Remarks]
  • URL: https://sites.google.com/site/kinoshitalabnagoya/
• [Remarks]
  • URL: http://www.nagoya-u.ac.jp/about-nu/public-relations/researchinfo/upload_images/20131011_sci.pdf
• [Remarks] Lab website
  • URL: https://sites.google.com/site/kinoshitalabnagoya/tasks
• [Remarks] Press release
  • URL: http://www.nagoya-u.ac.jp/about-nu/public-relations/researchinfo/upload_images/20131011_sci.pdf
• [Remarks]
  • URL: http://researchmap.jp/makotokinoshita
• [Remarks]
  • URL: https://sites.google.com/site/kinoshitalabnagoya/