Researcher Profile and Settings

Master

Affiliation (Master)

• Institute for Genetic Medicine　Pathophysiology

Affiliation (Master)

• Institute for Genetic Medicine　Pathophysiology

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Profile and Settings

Affiliation

• Hokkaido University, Institute for Genetic Medicine

Profile and Settings

• Name (Japanese)

  MOTEGI

• Name (Kana)

  FUMIO

• Name

  202101013497309229

Affiliation

• Hokkaido University, Institute for Genetic Medicine

Achievement

Research Interests

• Embryogenesis   Mechanobiology   Cell polarity   

Research Areas

• Life sciences / Biophysics / Mechanobiology
• Life sciences / Developmental biology / Embryogenesis
• Life sciences / Cell biology / Cell polarity

Research Experience

• 2020/10 - Today Institute for Genetic Medicine, Hokkaido University Developmental Physiology Professor
• 2012/08 - 2021/03 Dept. of Biological Sciences, Faculty of Science, National University of Singapore Assistant Professor
• 2012/08 - 2021/03 Mechanobiology Institute, National University of Singapore Principle Investigator
• 2012/08 - 2021/03 Temasek Lifesciences Laboratory Senior Principle Investigator
• 2007/08 - 2012/07 Johns Hopkins University School of Medicine Postdoctoral Researcher
• 2006/08 - 2007/07 UCSD Postdoctoral Researcher
• 2002/04 - 2006/07 RIKEN Center for Developmental Biology Postdoctoral Researcher

Education

• 1997/04 - 2002/03  The University of Tokyo  Graduate School of Arts and Sciences

Awards

• 2012 Singapore National Research Foundation Singapore National Research Foundation Fellowship
  
• 2010/05 Japan Society for Cell Biology Young Scientist Best Presentation Award
  

Published Papers

• Fluid flow dynamics in cellular patterning.

  Kenji Kimura, Fumio Motegi

  Seminars in cell & developmental biology 2021/07/14 

  The development of complex forms of multicellular organisms depends on the spatial arrangement of cellular architecture and functions. The interior design of the cell is patterned by spatially biased distributions of molecules and biochemical reactions in the cytoplasm and/or on the plasma membrane. In recent years, a dynamic change in the cytoplasmic fluid flow has emerged as a key physical process of driving long-range transport of molecules to particular destinations within the cell. Here, recent experimental advances in the understanding of the generation of the various types of cytoplasmic flows and contributions to intracellular patterning are reviewed with a particular focus on feedback mechanisms between the mechanical properties of fluid flow and biochemical signaling during animal cell polarization.
• A balance between antagonizing PAR proteins specifies the pattern of asymmetric and symmetric divisions in C. elegans embryogenesis.

  Yen Wei Lim, Fu-Lai Wen, Prabhat Shankar, Tatsuo Shibata, Fumio Motegi

  Cell reports 36 (1) 109326 - 109326 2021/07/06 

  Coordination between cell differentiation and proliferation during development requires the balance between asymmetric and symmetric modes of cell division. However, the cellular intrinsic cue underlying the choice between these two division modes remains elusive. Here, we show evidence in Caenorhabditis elegans that the invariable lineage of the division modes is specified by the balance between antagonizing complexes of partitioning-defective (PAR) proteins. By uncoupling unequal inheritance of PAR proteins from that of fate determinants during cell division, we demonstrate that changes in the balance between PAR-2 and PAR-6 can be sufficient to re-program the division modes from symmetric to asymmetric and vice versa in two daughter cells. The division mode adopted occurs independently of asymmetry in cytoplasmic fate determinants, cell-size asymmetry, and cell-cycle asynchrony between sister cells. We propose that the balance between PAR proteins represents an intrinsic self-organizing cue for the specification of the two division modes during development.
• Mechanochemical Control of Symmetry Breaking in the Caenorhabditis elegans Zygote

  Wan Jun Gan, Fumio Motegi

  Frontiers in Cell and Developmental Biology 8 2021/01/18 

  Cell polarity is the asymmetric organization of cellular components along defined axes. A key requirement for polarization is the ability of the cell to break symmetry and achieve a spatially biased organization. Despite different triggering cues in various systems, symmetry breaking (SB) usually relies on mechanochemical modulation of the actin cytoskeleton, which allows for advected movement and reorganization of cellular components. Here, the mechanisms underlying SB in Caenorhabditis elegans zygote, one of the most popular models to study cell polarity, are reviewed. A zygote initiates SB through the centrosome, which modulates mechanics of the cell cortex to establish advective flow of cortical proteins including the actin cytoskeleton and partitioning defective (PAR) proteins. The chemical signaling underlying centrosomal control of the Aurora A kinase–mediated cascade to convert the organization of the contractile actomyosin network from an apolar to polar state is also discussed.
• Novel approaches to link apicobasal polarity to cell fate specification

  Fumio Motegi, Nicolas Plachta, Virgile Viasnoff

  Current Opinion in Cell Biology 62 78 - 85 0955-0674 2020/02
• Aurora-A Breaks Symmetry in Contractile Actomyosin Networks Independently of Its Role in Centrosome Maturation

  Peng Zhao, Xiang Teng, Sarala Neomi Tantirimudalige, Masatoshi Nishikawa, Thorsten Wohland, Yusuke Toyama, Fumio Motegi

  Developmental Cell 48 (5) 631 - 645.e6 1534-5807 2019/03
• Establishment of the PAR-1 cortical gradient by the aPKC-PRBH circuit

  Ravikrishna Ramanujam, Ziyin Han, Zhen Zhang, Pakorn Kanchanawong, Fumio Motegi

  Nature Chemical Biology 14 (10) 917 - 927 1552-4450 2018/10
• TPXL-1 activates Aurora A to clear contractile ring components from the polar cortex during cytokinesis

  Sriyash Mangal, Jennifer Sacher, Taekyung Kim, Daniel Sampaio Osório, Fumio Motegi, Ana Xavier Carvalho, Karen Oegema, Esther Zanin

  Journal of Cell Biology 217 (3) 837 - 848 0021-9525 2018/03/05 

  During cytokinesis, a signal from the central spindle that forms between the separating anaphase chromosomes promotes the accumulation of contractile ring components at the cell equator, while a signal from the centrosomal microtubule asters inhibits accumulation of contractile ring components at the cell poles. However, the molecular identity of the inhibitory signal has remained unknown. To identify molecular components of the aster-based inhibitory signal, we developed a means to monitor the removal of contractile ring proteins from the polar cortex after anaphase onset. Using this assay, we show that polar clearing is an active process that requires activation of Aurora A kinase by TPXL-1. TPXL-1 concentrates on astral microtubules coincident with polar clearing in anaphase, and its ability to recruit Aurora A and activate its kinase activity are essential for clearing. In summary, our data identify Aurora A kinase as an aster-based inhibitory signal that restricts contractile ring components to the cell equator during cytokinesis.
• ImaEdge – a platform for quantitative analysis of the spatiotemporal dynamics of cortical proteins during cell polarization

  Zhen Zhang, Yen Wei Lim, Peng Zhao, Pakorn Kanchanawong, Fumio Motegi

  Journal of Cell Science 130 (24) 4200 - 4212 0021-9533 2017/12/15
• Forceful patterning in mouse preimplantation embryos

  Ravikrishna Ramanujam, Tricia Yu Feng Low, Yen Wei Lim, Fumio Motegi

  Seminars in Cell & Developmental Biology 71 129 - 136 1084-9521 2017/11
• Cortical forces and CDC-42 control clustering of PAR proteins for Caenorhabditis elegans embryonic polarization

  Shyi-Chyi Wang, Tricia Yu Feng Low, Yukako Nishimura, Laurent Gole, Weimiao Yu, Fumio Motegi

  Nature Cell Biology 19 (8) 988 - 995 1465-7392 2017/08 

  Cell polarization enables zygotes to acquire spatial asymmetry, which in turn patterns cellular and tissue axes during development. Local modification in the actomyosin cytoskeleton mediates spatial segregation of partitioning-defective (PAR) proteins at the cortex, but how mechanical changes in the cytoskeleton are transmitted to PAR proteins remains elusive. Here we uncover a role of actomyosin contractility in the remodelling of PAR proteins through cortical clustering. During embryonic polarization in Caenorhabditis elegans, actomyosin contractility and the resultant cortical tension stimulate clustering of PAR-3 at the cortex. Clustering of atypical protein kinase C (aPKC) is supported by PAR-3 clusters and is antagonized by activation of CDC-42. Cortical clustering is associated with retardation of PAR protein exchange at the cortex and with effective entrainment of advective cortical flows. Our findings delineate how cytoskeleton contractility couples the cortical clustering and long-range displacement of PAR proteins during polarization. The principles described here would apply to other pattern formation processes that rely on local modification of cortical actomyosin and PAR proteins.
• Cortical Polarity of the RING Protein PAR-2 Is Maintained by Exchange Rate Kinetics at the Cortical-Cytoplasmic Boundary

  Yukinobu Arata, Michio Hiroshima, Chan-Gi Pack, Ravikrishna Ramanujam, Fumio Motegi, Kenichi Nakazato, Yuki Shindo, Paul W. Wiseman, Hitoshi Sawa, Tetsuya J. Kobayashi, Hugo B. Brandão, Tatsuo Shibata, Yasushi Sako

  Cell Reports 17 (1) 316 - 316 2211-1247 2016/09
• Cortical Polarity of the RING Protein PAR-2 Is Maintained by Exchange Rate Kinetics at the Cortical-Cytoplasmic Boundary.

  Yukinobu Arata, Michio Hiroshima, Chan-Gi Pack, Ravikrishna Ramanujam, Fumio Motegi, Kenichi Nakazato, Yuki Shindo, Paul W Wiseman, Hitoshi Sawa, Tetsuya J Kobayashi, Hugo B Brandão, Tatsuo Shibata, Yasushi Sako

  Cell reports 16 (8) 2156 - 2168 2016/08/23 

  Cell polarity arises through the spatial segregation of polarity regulators. PAR proteins are polarity regulators that localize asymmetrically to two opposing cortical domains. However, it is unclear how the spatially segregated PAR proteins interact to maintain their mutually exclusive partitioning. Here, single-molecule detection analysis in Caenorhabditis elegans embryos reveals that cortical PAR-2 diffuses only short distances, and, as a result, most PAR-2 molecules associate and dissociate from the cortex without crossing into the opposing domain. Our results show that cortical PAR-2 asymmetry is maintained by the local exchange reactions that occur at the cortical-cytoplasmic boundary. Additionally, we demonstrate that local exchange reactions are sufficient to maintain cortical asymmetry in a parameter-free mathematical model. These findings suggest that anterior and posterior PAR proteins primarily interact through the cytoplasmic pool and not via cortical diffusion.
• The PAR network: redundancy and robustness in a symmetry-breaking system

  Fumio Motegi, Geraldine Seydoux

  Philosophical Transactions of the Royal Society B: Biological Sciences 368 (1629) 20130010 - 20130010 0962-8436 2013/11/05 

  To become polarized, cells must first ‘break symmetry’. Symmetry breaking is the process by which an unpolarized, symmetric cell develops a singularity, often at the cell periphery, that is used to develop a polarity axis. The Caenorhabditis elegans zygote breaks symmetry under the influence of the sperm-donated centrosome, which causes the PAR polarity regulators to sort into distinct anterior and posterior cortical domains. Modelling analyses have shown that cortical flows induced by the centrosome combined with antagonism between anterior and posterior PARs (mutual exclusion) are sufficient, in principle, to break symmetry, provided that anterior and posterior PAR activities are precisely balanced. Experimental evidence indicates, however, that the system is surprisingly robust to changes in cortical flows, mutual exclusion and PAR balance. We suggest that this robustness derives from redundant symmetry-breaking inputs that engage two positive feedback loops mediated by the anterior and posterior PAR proteins. In particular, the PAR-2 feedback loop stabilizes the polarized state by creating a domain where posterior PARs are immune to exclusion by anterior PARs. The two feedback loops in the PAR network share characteristics with the two feedback loops in the Cdc42 polarization network of Saccharomyces cerevisiae .
• Microtubules induce self-organization of polarized PAR domains in Caenorhabditis elegans zygotes

  Fumio Motegi, Seth Zonies, Yingsong Hao, Adrian A Cuenca, Erik Griffin, Geraldine Seydoux

  Nature Cell Biology 13 (11) 1361 - 1367 2011/10 [Refereed]
  
• Basement membrane sliding and targeted adhesion remodels tissue boundaries during uterine–vulval attachment in Caenorhabditis elegans

  Shinji Ihara, Elliott J. Hagedorn, Meghan A. Morrissey, Qiuyi Chi, Fumio Motegi, James M. Kramer, David R. Sherwood

  Nature Cell Biology 13 (6) 641 - 651 1465-7392 2011/06
• Cytoplasmic Partitioning of P Granule Components Is Not Required to Specify the Germline in C. elegans

  C. M. Gallo, J. T. Wang, F. Motegi, G. Seydoux

  Science 330 (6011) 1685 - 1689 0036-8075 2010/12/17
• Caenorhabditis elegans ortholog of the p24/p22 subunit, DNC-3, is essential for the formation of the dynactin complex by bridging DNC-1/p150(Glued) and DNC-2/dynamitin

  Masahiro Terasawa, Mika Toya, Fumio Motegi, Miyeko Mana, Kuniaki Nakamura, Asako Sugimoto

  Genes to Cells 15 (11) 1145 - 1157 2010/11
• Symmetry breaking and polarization of the C. elegans zygote by the polarity protein PAR-2

  S. Zonies, F. Motegi, Y. Hao, G. Seydoux

  Development 137 (10) 1669 - 1677 0950-1991 2010/05/15
• A new mechanism controlling kinetochore-microtubule interactions revealed by comparison of two dynein-targeting components: SPDL-1 and the Rod/Zwilch/Zw10 complex

  R. Gassmann, A. Essex, J.-S. Hu, P. S. Maddox, F. Motegi, A. Sugimoto, S. M. O'Rourke, B. Bowerman, I. McLeod, J. R. Yates, K. Oegema, I. M. Cheeseman, A. Desai

  Genes & Development 22 (17) 2385 - 2399 0890-9369 2008/09/01
• Revisiting the role of microtubules in C. elegans polarity.

  Motegi F, Seydoux G

  Journal of Cell Biology 179 (3) 367 - 369 2007/11
• Function of microtubules at the onset of cytokinesis

  Fumio Motegi, Asako Sugimoto

  Tanpakusitu Kakusan Koso 51 1590 - 1595 2006/09
• Sequential functioning of the ECT-2 RhoGEF, RHO-1 and CDC-42 establishes cell polarity in Caenorhabditis elegans embryos

  Fumio Motegi, Asako Sugimoto

  Nature Cell Biology 8 (9) 978 - 985 1465-7392 2006/09
• Cell polarization: lessons from C. elegans asymmetric cell division

  Fumio Motegi, Asako Sugimoto

  Tanpakushitsu Kakusan Koso 51 776 - 781 2006/05
• Two phases of astral microtubule activity during cytokinesis in C. elegans embryos

  Motegi F, Velarde NV, Piano F, Sugimoto A

  Developmental Cell 10 (4) 509 - 520 2006/04
• Myosin-II reorganization during mitosis is controlled temporally by its dephosphorylation and spatially by Mid1 in fission yeast

  Fumio Motegi, Mithilesh Mishra, Mohan K. Balasubramanian, Issei Mabuchi

  Journal of Cell Biology 165 (5) 685 - 695 0021-9525 2004/06/07 

  Cytokinesis in many eukaryotes requires an actomyosin contractile ring. Here, we show that in fission yeast the myosin-II heavy chain Myo2 initially accumulates at the division site via its COOH-terminal 134 amino acids independently of F-actin. The COOH-terminal region can access to the division site at early G2, whereas intact Myo2 does so at early mitosis. Ser1444 in the Myo2 COOH-terminal region is a phosphorylation site that is dephosphorylated during early mitosis. Myo2 S1444A prematurely accumulates at the future division site and promotes formation of an F-actin ring even during interphase. The accumulation of Myo2 requires the anillin homologue Mid1 that functions in proper ring placement. Myo2 interacts with Mid1 in cell lysates, and this interaction is inhibited by an S1444D mutation in Myo2. Our results suggest that dephosphorylation of Myo2 liberates the COOH-terminal region from an intramolecular inhibition. Subsequently, dephosphorylated Myo2 is anchored by Mid1 at the medial cortex and promotes the ring assembly in cooperation with F-actin.
• Importance of a Myosin II-Containing Progenitor for Actomyosin Ring Assembly in Fission Yeast

  Kelvin C.Y. Wong, Ventris M. D'souza, Naweed I. Naqvi, Fumio Motegi, Issei Mabuchi, Mohan K. Balasubramanian

  Current Biology 12 (9) 724 - 729 0960-9822 2002/04
• Contractile ring formation in Xenopus egg and fission yeast

  Noguchi T, Arai R, Motegi F, Nakano K, Mabuchi I

  Cell Structure and Function 26 (6) 545 - 554 2001/12
• Identification of two type V myosins in fission yeast, one of which functions in polarized cell growth and moves rapidly in the cell.

  Motegi F, Arai R, Mabuchi I

  Molecular Biology of the Cell 12 (5) 1367 - 1380 2001/05
• Identification and functional analysis of the gene for type I myosin in fission yeast

  Toya M, Motegi F, Nakano K, Mabuchi I, Yamamoto M

  Genes to Cells 62 (3) 187 - 199 2001/03
• The S. pombe rlc1 gene encodes a putative myosin regulatory light chain that binds the type II myosins myo3p and myo2p

  Le Goff, Motegi F, Salimova E, Mabuchi I, Simanis V

  113 4157 - 4163 2000/12
• Molecular mechanism of myosin-II assembly at the division site in Schizosaccharomyces pombe

  F Motegi, K Nakano, I Mabuchi

  Journal of Cell Science 113 1813 - 1825 2000/05
• Overproduction of elongation factor 1α, an essential translational component, causes aberrant cell morphology by affecting the control of growth polarity in fission yeast

  Masako Suda, Mikiko Fukui, Yuki Sogabe, Kazuhito Sato, Akeshi Morimatsu, Ritsuko Arai, Fumio Motegi, Tokichi Miyakawa, Issei Mabuchi, Dai Hirata

  Genes to Cells 4 (9) 517 - 527 1356-9597 1999/09
• Identification of Myo3, a second type-II myosin heavy chain in the fission yeast Schizosaccharomyces pombe

  Fumio Motegi, Kentaro Nakano, Chikako Kitayama, Masayuki Yamamoto, Issei Mabuchi

  FEBS Letters 420 (2-3) 161 - 166 0014-5793 1997/12/29

Books etc

• ラボレポート独立編: 在新加坡的自立門户之路: シンガポールで独立してみた

  茂木文夫 
  実験医学 2019/06

Research Projects

• Mechanical self-transformation of living systems

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2022/06 -2027/03 

  Author : 茂木 文夫, 柊 卓志, 見学 美根子, 柴田 達夫, 近藤 武史, Phng LiKun, 吉村 成弘
• 光温度遺伝学を活用した生体の自律的パターン形成の解析

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2022/04 -2025/03 

  Author : 茂木 文夫
• 微小管メカニクスが誘導する細胞極性パターニング

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2021/10 -2025/03 

  Author : 茂木 文夫, 西村 有香子, 木戸秋 悟, 柴田 達夫, 多羅間 充輔

   

  生体内の細胞は、細胞内外に作用する機械的力を利用して、細胞極性の非対称パターンを獲得することが示されたが、この過程で力刺激を感知・応答する分子機構は未だに不明な点が多い。本研究は、細胞骨格である「微小管」のメカニクスを中心とするメカノトランスダクション機構が、細胞極性の非対称パターンを誘導する機構を包括的に理解することを目標とする。 本提案研究では、線虫初期胚とヒト培養細胞を対象とし、細胞内微小管の構造と機能を人為操作する実験手法を確立し、この微小管メカニクスの変動が細胞極性パターンの誘導と維持に及ぼす影響を高解像度ライブイメージングにより解析する。線虫初期胚では、細胞内温度変化によって微小管（チューブリン）、微小管形成中心（中心体）、または微小管モーター（ダイニン複合体）の機能を操作する株を作成し、温度変化と同時にライブイメージングを可能な実験系を確立した。ヒト培養細胞では、メカノトランスダクション構造である細胞接着斑と微小管の相互作用を操作する化学遺伝学手法を確立し、更にこの技術を改変した光遺伝学的手法を開発している。更に、細胞接着斑のメカノトランスダクション機能を操作するために、細胞外基質の機械的性質を微細加工する技術を構築している。今後はこれらの手法を組み合わせて、微小管と細胞外環境のメカニクスを人為操作する技術を確立し、微小管の高速高解像度ライブイメージングと画像解析・数理解析を融合した学際的研究戦略によって、細胞極性化における微小管メカニクスの生理的意義を解明する。
• 体系的RNAi法を利用した線虫C.elegansにおける微小管制御因子の解析

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2003 -2004 

  Author : 茂木 文夫

   

  微小管は主にセントロソームで形成され、分裂期にはその構造をダイナミックに変化させるが、微小管のダイナミクスを調節する機構および微小管による細胞分裂の制御機構については未だ理解が進んでいない。RNA干渉法を用いて線虫初期胚の微小管形成にはたらく因子を探索した結果、セントロソームに局在することが知られているγ-tubulin (TBG-1)およびaurora kinase A (AIR-1)は、セントロソームにおける微小管形成に並列に寄与していることを明らかにした。さらに、TBG-1依存的な微小管とAIR-1依存的な微小管では細胞表層の収縮へのはたらきかけが異なることが示された。TBG-1欠損胚でみられるAIR-1依存的な微小管は、細胞表層へと到達した後にも伸長を続け、anaphase後期にみられる細胞表層の収縮を抑制した。一方、AIR-1欠損胚でみられるTBG-1依存的な微小管は、細胞表層に到達すると短縮・伸長を繰り返し、anaphase初期に細胞表層の収縮を促進した。このことから、TBG-1とAIR-1は、セントロソームにおける微小管形成を介して、細胞表層の収縮に対して相反する役割を示すことが示唆された。つぎに、野生型初期胚の微小管動態の観察を行った結果、anaphase初期の分裂面周辺の細胞表層にはTBG-1依存的微小管と類似した短縮・伸長を繰り返す微小管が集積していたのに対して、anaphase後期には分裂面以外の細胞表層に伸長を続けるAIR-1依存的微小管と類似した微小管が観察された。以上の結果から、細胞質分裂における細胞表層の収縮性制御には、TBG-1およびAIR-1が関与する二つの独立の微小管制御機構が働いている可能性が考えられる。