Analysis of neuron migration mechanism using brain microspace reproduced by new materials and microfabrication technology

• Project/Area Number: 18KK0212
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 46:Neuroscience and related fields
• Research Institution: Kyoto University
• Principal Investigator: Kengaku Mineko 京都大学, 高等研究院, 教授 (10303801)
• Co-Investigator(Kenkyū-buntansha): 宇都 甲一郎 国立研究開発法人物質・材料研究機構, 機能性材料研究拠点, 独立研究者 (30597034) ; 中澤 直高 京都大学, 高等研究院, 特定助教 (90800780)
• Project Period (FY): 2018-10-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2021: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: メカノバイオロジー / マイクロファブリケーション / ニューロン移動 / 神経発生 / 細胞骨格 / ライブイメージング

Outline of Final Research Achievements

Newly born neurons migrate in crowded brain tissue to their individual sites of function in the developing cortex. This study explored the mechanism by which neurons sense the local physical environment and generate cytoskeletal force to pass through the confined 3-dimentional space. We organized an interdisciplinary team to elucidate the novel mechanism of neuronal migration. We designed micropatterned substrates mimicking the size and geometry of interstitial space of the developing brain tissue and observed cytoskeletal dynamics during confined migration at a high spatiotemporal resolution. Pharmacological and molecular perturbation analyses clarified that the increase in plasma membrane tension activated a mechanosensitive channel PIEZO1. PIEZO1-induced calcium influx triggered the PKC-ezrin cascade, which recruited actomyosin and transmitted its contractile force to the posterior plasma membrane. Our results demonstrate a novel mechano-sensing mechanism of neuronal migration.

Academic Significance and Societal Importance of the Research Achievements

これまでニューロン遊走は細胞種により異なる細胞機構で制御されると考えられてきたが、本研究でニューロンが細胞外の物理環境を読み取り、複数の分子経路のうち最適な力発生機構を動員することが明らかになった。この発見はニューロン遊走機構の概念を変えるもので、ニューロン遊走の異常を伴う先天的脳奇形や精神神経疾患の病因解明に繋がる可能性もある。また本研究で開発したマイクロ加工デバイスは、様々な遊走性細胞における物性制御の解析にも応用でき、脳発生・変性過程の多くの問題に新しいパラダイムと方法論を提供するものである。

Research Products

• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Journal Article] Modeling intestinal stem cell function with organoids (2021)
  • Author(s): Toshio Takahashi, Kazuo Fujishima, and Mineko Kengaku
  • Journal Title: Int. J. Mol. Sci. Volume: 22 Issue: 20 Pages: 1-14
  • DOI: 10.3390/ijms222010912
  • Peer Reviewed / Open Access
• [Journal Article] ABCA13 dysfunction associated with psychiatric disorders causes impaired cholesterol trafficking (2021)
  • Author(s): Nakato Mitsuhiro、Shiranaga Naoko、Tomioka Maiko、Watanabe Hitomi、Kurisu Junko、Kengaku Mineko、Komura Naoko、Ando Hiromune、Kimura Yasuhisa、Kioka Noriyuki、Ueda Kazumitsu
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100166-100166
  • DOI: 10.1074/jbc.ra120.015997
  • NAID: 120007177776
  • Peer Reviewed / Open Access
• [Journal Article] βIII spectrin controls the planarity of Purkinje cell dendrites by modulating perpendicular axon-dendrite interactions (2020)
  • Author(s): Fujishima Kazuto、Kurisu Junko、Yamada Midori、Kengaku Mineko
  • Journal Title: Development Volume: 147 Issue: 24
  • DOI: 10.1242/dev.194530
  • Peer Reviewed / Open Access
• [Journal Article] Mechanical regulation of nuclear translocation in migratory neurons (2020)
  • Author(s): N. Nakazawa and M. Kengaku
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 8 Pages: 150-150
  • DOI: 10.3389/fcell.2020.00150
  • NAID: 120006813309
  • Peer Reviewed / Open Access
• [Presentation] Cytoskeletal forces driving neuronal migration in 3D brain tissues. (2022)
  • Author(s): Mineko Kengaku
  • Organizer: International Symposium on Development and Plasticity of Neural Systems
  • Int'l Joint Research / Invited
• [Presentation] 幹細胞機能に関わる動的力学特性を制御可能なハイドロゲルの設計 (2022)
  • Author(s): 谷本梨帆、荏原充宏、宇都甲一郎
  • Organizer: 第21回日本再生医療学会総会
• [Presentation] Multiple engines driving nuclear migration in neurons during brain development. (2021)
  • Author(s): Mineko Kengaku
  • Organizer: RIMS Workshop Mathematical Mechanobiology
  • Int'l Joint Research / Invited
• [Presentation] ライブイメージングで解くニューロン遊走における核輸送の制御機構 (2021)
  • Author(s): 見学美根子
  • Organizer: 第64回日本神経化学会大会
  • Invited
• [Presentation] Mechanical stress by extracellular confinement triggers a mode transition of neuronal migration. (2021)
  • Author(s): Naotaka Nakazawa, Gianluca Grenci and Mineko Kengaku
  • Organizer: Materials, Mimics, and Microfluidics: Engineering Tools for Mechanobiology
  • Int'l Joint Research / Invited
• [Presentation] Nesprin-2 mediates bidirectional nuclear transport through a co-dependent interplay between dynein and kinesin-1 in migrating cerebellar granule neurons. (2021)
  • Author(s): Chuying Zhou, You Kure Wu, Takahiro Fujiwara, Mineko Kengaku
  • Organizer: 第44回日本神経科学大会
• [Presentation] Oscillation of AMPK activity regulates mitochondrial fission and dendritic development in hippocampal neurons. (2021)
  • Author(s): 初田茜、藤島和人、栗栖純子、大野伸彦、見学美根子
  • Organizer: 第44回日本神経科学大会
• [Presentation] 幹細胞機能操作のための酵素分解性ハイドロゲルの設計 (2021)
  • Author(s): 谷本梨帆、荏原充宏、宇都甲一郎
  • Organizer: 第16回ナノ・バイオメディカル学会大会
• [Presentation] Design of enzymatically degradable hydrogels for unraveling the dynamic mechanical response of human mesenchymal stem cells (2021)
  • Author(s): Riho Tanimoto, Mitsuhiro Ebara, Koichiro Uto
  • Organizer: 第31回日本MRS年次大会
• [Presentation] ヒト間葉系幹細胞の力学応答解明に向けた酵素分解性ハイドロゲルの設計 (2021)
  • Author(s): 谷本梨帆、荏原充宏、宇都甲一郎
  • Organizer: 第70回高分子討論会
• [Presentation] Design of enzymatically degradable hydrogels for maneuvering the human mesenchymal stem cells behavior (2021)
  • Author(s): Riho Tanimoto, Mitsuhiro Ebara, Koichiro Uto
  • Organizer: MANA International Symposium 2021
  • Int'l Joint Research
• [Presentation] Neuronal migration in 3D brain tissue. (2020)
  • Author(s): 見学美根子
  • Organizer: 第14回ニッチ脳神経脈管カンファレンス
  • Invited
• [Presentation] Mechanical stress by extracellular confinement trigger a mode transition of neuronal migration. (2020)
  • Author(s): Naotaka Nakazawa, Gianluca Grenci, Mineko Kengaku
  • Organizer: 第58回日本生物物理学会年会
• [Presentation] Beta IIIスペクトリンのプルキンエ細胞-平行線維間の直交回路形成における役割. (2020)
  • Author(s): 藤島和人、見学美根子
  • Organizer: 第43回日本神経科学大会
• [Presentation] The dynamic interplay between microtubule-based motors and nuclear movement in migrating cerebellar granule cells. (2020)
  • Author(s): Chuying Zhou, You Kure Wu, Mineko Kengaku
  • Organizer: 第43回日本神経科学大会
• [Presentation] Cytoskeletal regulation of Purkinje cell dendritic arbor morphology. プルキンエ細胞樹状突起形態形成の細胞骨格制御メカニズム (2020)
  • Author(s): Kazuto Fujishima, Mineko Kengaku
  • Organizer: 第53回日本発生生物年会
• [Presentation] Mechanical stress by extracellular confinement trigger a mode transition of neuronal migration. (2019)
  • Author(s): Naotaka Nakazawa, Gianluca Grenci, Mineko Kengaku
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] Nuclear Migration in 3D Brain Tissue Driven by Cytoskeletal Forces. (2019)
  • Author(s): You Kure Wu, Chuying Zhou, Hiroki Umeshima, Naotaka Nakazawa and Mineko Kengaku
  • Organizer: 20th LSACJ2019-International Conference on Interdisciplinary Life Sciences
  • Int'l Joint Research / Invited
• [Presentation] 微小間隙を遊走するニューロンのメカノレスポンス (2019)
  • Author(s): 中澤直高
  • Organizer: メカノバイオロジー研究を学ぶ 2019
  • Invited
• [Presentation] Cytoskeletal forces driving nuclear migration in developing neurons. (2019)
  • Author(s): Mineko Kengaku, You Kure Wu, Naotaka Nakazawa, Gianluca Grenci
  • Organizer: The 10th IBRO World Congress of Neuroscience
  • Int'l Joint Research / Invited
• [Presentation] Cell-extrinsic control of dendritic tree patterns of the cerebellar Purkinje cell. (2019)
  • Author(s): Kazuto Fujishima, Kelly Kawabata-Galbraith and Mineko Kengaku
  • Organizer: Current Trends and Future Directions of Synapse-Circuit Plasticity Research
  • Invited
• [Presentation] Mechano-responses to the extracellular environment in migratory neurons. (2019)
  • Author(s): 中澤直高、Gianluca Grenci、見学美根子
  • Organizer: 日本メカノバイオロジー研究会2019
  • Invited
• [Presentation] 発生中のニューロン核移動を制御する細胞骨格モーターの力発生機構. Mechanisms of force generation by cytoskeletal motors during nuclear migration of developing neurons. (2019)
  • Author(s): 見学美根子
  • Organizer: 第52回日本発生生物学会年会
  • Invited
• [Presentation] Cytoskeletal control of neuronal migration in the developing brain. (2019)
  • Author(s): Mineko Kengaku
  • Organizer: The SPIRITS International Symposium-2019 Regulation of cell fate and disease treatment
  • Int'l Joint Research / Invited
• [Presentation] Mechano-responses to the extracellular environment in migratory neurons. (2019)
  • Author(s): Naotaka Nakazawa
  • Organizer: 3rd International Symposium on Nanoarchitectonics for Mechanobiology
  • Int'l Joint Research / Invited
• [Presentation] High-resolution Imaging of Neuronal Migration in the Developing Brain. (2018)
  • Author(s): Mineko Kengaku
  • Organizer: Kyoto University-UCLA/25th iCeMS International Symposium “Harnessing Physical Forces for Medical Application: Convergence of Physics, Nanomaterials, Cell Biology and Cancer Research”
  • Int'l Joint Research / Invited