Updated on 2022/04/12

写真a

 
HOSOKAWA Tomohisa
 
Organization
Graduate School of Science Lecturer
Graduate School
Graduate School of Science
Undergraduate School
School of Science Department of Biological Science
Title
Lecturer
External link

Degree 1

  1. 博士(理学) ( 2010.3   東京都立大学 ) 

Research Interests 4

  1. Cell biology

  2. Neuroscience

  3. Biochemistry

  4. Molecular biology

Research Areas 1

  1. Life Science / Neuroscience-general

 

Papers 6

  1. CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation. International journal

    Tomohisa Hosokawa, Pin-Wu Liu, Qixu Cai, Joana S Ferreira, Florian Levet, Corey Butler, Jean-Baptiste Sibarita, Daniel Choquet, Laurent Groc, Eric Hosy, Mingjie Zhang, Yasunori Hayashi

    Nature neuroscience   Vol. 24 ( 6 ) page: 777 - 785   2021.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Transient information input to the brain leads to persistent changes in synaptic circuits, contributing to the formation of memory engrams. Pre- and postsynaptic structures undergo coordinated functional and structural changes during this process, but how such changes are achieved by their component molecules remains largely unknown. We found that activated CaMKII, a central player of synaptic plasticity, undergoes liquid-liquid phase separation with the NMDA-type glutamate receptor subunit GluN2B. Due to CaMKII autophosphorylation, the condensate stably persists even after Ca2+ is removed. The selective binding of activated CaMKII with GluN2B cosegregates AMPA receptors and the synaptic adhesion molecule neuroligin into a phase-in-phase assembly. In this way, Ca2+-induced liquid-liquid phase separation of CaMKII has the potential to act as an activity-dependent mechanism to crosslink postsynaptic proteins, which may serve as a platform for synaptic reorganization associated with synaptic plasticity.

    DOI: 10.1038/s41593-021-00843-3

    Web of Science

    Scopus

    PubMed

  2. Regulation of the Stability and Localization of Post-synaptic Membrane Proteins by Liquid-Liquid Phase Separation

    Hosokawa Tomohisa, Liu Pin-Wu

    FRONTIERS IN PHYSIOLOGY   Vol. 12   page: 795757   2021.12

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    Language:Japanese   Publisher:Frontiers in Physiology  

    Synaptic plasticity is a cellular mechanism of learning and memory. The synaptic strength can be persistently upregulated or downregulated to update the information sent to the neuronal network and form a memory engram. For its molecular mechanism, the stability of α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate-type glutamate receptor (AMPAR), a glutamatergic ionotropic receptor, on the postsynaptic membrane has been studied for these two decades. Since AMPAR is not saturated on the postsynaptic membrane during a single event of neurotransmitter release, the number and nanoscale localization of AMPAR is critical for regulating the efficacy of synaptic transmission. The observation of AMPAR on the postsynaptic membrane by super-resolution microscopy revealed that AMPAR forms a nanodomain that is defined as a stable segregated cluster on the postsynaptic membrane to increase the efficacy of synaptic transmission. Postsynaptic density (PSD), an intracellular protein condensate underneath the postsynaptic membrane, regulates AMPAR dynamics via the intracellular domain of Stargazin, an auxiliary subunit of AMPAR. Recently, it was reported that PSD is organized by liquid-liquid phase separation (LLPS) to form liquid-like protein condensates. Furthermore, the calcium signal induced by the learning event triggers the persistent formation of sub-compartments of different protein groups inside protein condensates. This explains the formation of nanodomains via synaptic activation. The liquid-like properties of LLPS protein condensates are ideal for the molecular mechanism of synaptic plasticity. In this review, we summarize the recent progress in the properties and regulation of synaptic plasticity, postsynaptic receptors, PSD, and LLPS.

    DOI: 10.3389/fphys.2021.795757

    Web of Science

    Scopus

    PubMed

  3. Regulation of synaptic nanodomain by liquid-liquid phase separation: A novel mechanism of synaptic plasticity. International journal

    Pin-Wu Liu, Tomohisa Hosokawa, Yasunori Hayashi

    Current opinion in neurobiology   Vol. 69   page: 84 - 92   2021.8

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Advances in microscopy techniques have revealed the details of synaptic nanodomains as defined by the segregation of specific molecules on or beneath both presynaptic and postsynaptic membranes. However, it is yet to be clarified how such segregation is accomplished without demarcating membrane and how nanodomains respond to the neuronal activity. It was recently discovered that proteins at the synapse undergo liquid-liquid phase separation (LLPS), which not only contributes to the accumulation of synaptic proteins but also to further segregating the proteins into subdomains by forming phase-in-phase structures. More specifically, CaMKII, a postsynaptic multifunctional kinase that serves as a signaling molecule, acts as a synaptic cross-linker which segregates certain molecules through LLPS in a manner triggered by Ca2+. Nanodomain formation contributes to the establishment of trans-synaptic nanocolumns, which may be involved in the optimization of spatial arrangement of the transmitter release site and receptor, thereby serving as a new mechanism of synaptic plasticity.

    DOI: 10.1016/j.conb.2021.02.004

    Web of Science

    PubMed

  4. Arc self-association and formation of virus-like capsids are mediated by an N-terminal helical coil motif. International journal

    Maria S Eriksen, Oleksii Nikolaienko, Erik I Hallin, Sverre Grødem, Helene J Bustad, Marte I Flydal, Ian Merski, Tomohisa Hosokawa, Daniela Lascu, Shreeram Akerkar, Jorge Cuéllar, James J Chambers, Rory O'Connell, Gopinath Muruganandam, Remy Loris, Christine Touma, Tambudzai Kanhema, Yasunori Hayashi, Margaret M Stratton, José M Valpuesta, Petri Kursula, Aurora Martinez, Clive R Bramham

    The FEBS journal   Vol. 288 ( 9 ) page: 2930 - 2955   2021.5

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    Language:English   Publishing type:Research paper (scientific journal)  

    Activity-regulated cytoskeleton-associated protein (Arc) is a protein interaction hub with diverse roles in intracellular neuronal signaling, and important functions in neuronal synaptic plasticity, memory, and postnatal cortical development. Arc has homology to retroviral Gag protein and is capable of self-assembly into virus-like capsids implicated in the intercellular transfer of RNA. However, the molecular basis of Arc self-association and capsid formation is largely unknown. Here, we identified a 28-amino-acid stretch in the mammalian Arc N-terminal (NT) domain that is necessary and sufficient for self-association. Within this region, we identified a 7-residue oligomerization motif, critical for the formation of virus-like capsids. Purified wild-type Arc formed capsids as shown by transmission and cryo-electron microscopy, whereas mutant Arc with disruption of the oligomerization motif formed homogenous dimers. An atomic-resolution crystal structure of the oligomerization region peptide demonstrated an antiparallel coiled-coil interface, strongly supporting NT-NT domain interactions in Arc oligomerization. The NT coil-coil interaction was also validated in live neurons using fluorescence lifetime FRET imaging, and mutation of the oligomerization motif disrupted Arc-facilitated endocytosis. Furthermore, using single-molecule photobleaching, we show that Arc mRNA greatly enhances higher-order oligomerization in a manner dependent on the oligomerization motif. In conclusion, a helical coil in the Arc NT domain supports self-association above the dimer stage, mRNA-induced oligomerization, and formation of virus-like capsids. DATABASE: The coordinates and structure factors for crystallographic analysis of the oligomerization region were deposited at the Protein Data Bank with the entry code 6YTU.

    DOI: 10.1111/febs.15618

    PubMed

  5. Shank3 Binds to and Stabilizes the Active Form of Rap1 and HRas GTPases via Its NTD-ANK Tandem with Distinct Mechanisms Reviewed

    Qixu Cai, Tomohisa Hosokawa, Menglong Zeng, Yasunori Hayashi, Mingjie Zhang

    Structure   Vol. 28 ( 3 ) page: 290 - 300.e4   2020.3

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    Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.str.2019.11.018

  6. Structure of monomeric full-length ARC sheds light on molecular flexibility, protein interactions, and functional modalities. Reviewed

    Hallin EI, Eriksen MS, Baryshnikov S, Nikolaienko O, Grødem S, Hosokawa T, Hayashi Y, Bramham CR, Kursula P

    J Neurochem. 2018 Nov;147(3):323-343. doi: 10.1111/jnc.14556. Epub 2018 Sep 26.   Vol. 147 ( 3 ) page: 323 - 343   2018.11

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    Language:English   Publishing type:Research paper (scientific journal)  

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Presentations 2

  1. シナプス機能研究の新展開 Invited

    細川智永

    日本生理学会大会  2017.3 

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    Language:English  

  2. 液-液相分離によるシナプス後膜肥厚のカルシウム依存的かつ可塑的な蛋白質集合体の形成 Invited

    細川 智永, 劉 品吾, 木下 専, 林 康紀

    第44回日本神経科学会  2021.7.29 

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    Language:English   Presentation type:Symposium, workshop panel (public)  

Research Project for Joint Research, Competitive Funding, etc. 2

  1. LLPSの生化学実験

    Grant number:2521JC215c  2021.4 - 2023.3

    CREST 

    細川智永

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\7000000

  2. 神経ネットワークを自由に操作することを目指した、シナプス内部構造の 形成機構と再構築

    Grant number:2520000560  2020.9 - 2024.3

    ヴィジョナリーリサーチ 

    細川智永

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    Authorship:Principal investigator 

    Grant amount:\1920000

KAKENHI (Grants-in-Aid for Scientific Research) 3

  1. 記憶形成に伴うシナプスタンパク質の集積・維持の制御機構

    Grant number:21H02595  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(B)

    実吉 岳郎, 細川 智永

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    Authorship:Coinvestigator(s) 

    記憶の基盤であるシナプス可塑性の誘導・発現機構は詳細に検討されているが、刺激後にシナプス強度を維持する仕組みについてはほとんど明らかになっていない。本研究は、記憶の細胞レベルの現象である長期増強現象に伴うシナプスタンパク質のダイナミクスを生物学的相分離で説明することを目指している。In vitroでの実験の結果を神経細胞へと還元することで記憶形成に伴う分子のシナプス微小空間での動態を明らかにすることを目的とする。

  2. Reconstitution of synaptic plasticity in vitro

    Grant number:19K06885  2019.4 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Authorship:Principal investigator 

    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

  3. Structural role of CaMKII in PSD and the induction of LTP by optpgenetics.

    Grant number:18KK0421  2019 - 2021

    Grants-in-Aid for Scientific Research  Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))

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    Authorship:Principal investigator 

    Grant amount:\13000000 ( Direct Cost: \10000000 、 Indirect Cost:\3000000 )

 

Teaching Experience (On-campus) 2

  1. 生理・解剖学2

    2021

  2. 生物学基礎II

    2021