研究者基本情報

• 博士（工学）, 東京大学

• https://researchmap.jp/nmrmt

• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201801012693373359

• 201801012693373359

• 神経科学

• ライフサイエンス, 細胞生物学

• 修士課程, 生命科学院
• 博士課程, 生命科学院

研究活動情報

• MAVS phosphorylation acts as a cellular stress sensor that modulates antiviral immunity.
  Dongyi Zhao; Nao Morimoto; Riho Saito; Juri Yamada; Shuntaro Abe; Hidetaka Kosako; Yukiko Gotoh; Tomohiko Okazaki
  iScience, 28, 9, 113256, 113256, 2025年09月19日, ［国際誌］
  英語, 研究論文（学術雑誌）, Upon viral infection, cytosolic RIG-I-like receptors recognize viral RNA and activate innate immune responses through the mitochondrial antiviral-signaling protein (MAVS), leading to type I interferon (IFN) production and apoptosis. Cellular stress influences immune activation, but its impact on MAVS signaling remains largely unclear. Here, we show that MAVS undergoes phosphorylation via p38 MAPK signaling, activated by the stress-activated MAPKKK ASK1. This modification enhances MAVS interaction with TRAF, a key downstream adaptor, thereby promoting type I IFN induction. Oxidative and endoplasmic reticulum stress significantly amplified type I IFN expression upon viral infection, but this effect was attenuated in cells expressing MAVS mutants lacking phosphorylation sites. These findings suggest MAVS phosphorylation as a key mechanism integrating cellular stress signals into antiviral immunity. By linking the MAPK pathway to MAVS-dependent IFN expression, we propose MAVS phosphorylation as a cellular stress sensor that modulates antiviral immunity in a context-dependent manner.
• Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense.
  Tomohiko Okazaki; Keiji Nozaki; Nao Morimoto; Yuta Otobe; Riho Saito; Shuntaro Abe; Miyuki Okajima; Hikari Yoshitane; Tomohisa Hatta; Shun-Ichiro Iemura; Tohru Natsume; Hidetaka Kosako; Miwako Yamasaki; Satoshi Inoue; Takashi Kondo; Haruhiko Koseki; Yukiko Gotoh
  Science (New York, N.Y.), 389, 6755, 84, 91, 2025年07月03日, ［国際誌］
  英語, 研究論文（学術雑誌）, Mitochondrial antiviral signaling protein (MAVS) is an adaptor involved in antiviral immunity, but its regulation is not fully understood. We identified carboxylation of MAVS by vitamin K (VK)-dependent γ-glutamyl carboxylase (GGCX), which was unexpected owing to the reported membrane topology of GGCX. We found that GGCX could undergo topology inversion to carboxylate MAVS within the cytoplasm. This carboxylation enhanced the ability of MAVS to induce type I interferons while suppressing the induction of apoptosis. Genetic knockout of GGCX, a VK-free diet, or depletion of VK by inhibiting VK epoxide reductase 1 with warfarin increased viral susceptibility in mice. Thus, we identified a MAVS regulatory mechanism-the existence of cytoplasmic protein carboxylation and topological inversion of GGCX-and demonstrated how modulating VK levels may influence antiviral defense.
• Evolutionary engineering and characterization of Sendai virus mutants capable of persistent infection and autonomous production
  Moe Iwata; Ryoko Kawabata; Nao Morimoto; Ryosuke F. Takeuchi; Takemasa Sakaguchi; Takashi Irie; Fumitaka Osakada
  Frontiers in Virology, 4, Frontiers Media SA, 2024年04月02日
  研究論文（学術雑誌）, Persistent virus infection involves modifying the host immune response and maintaining viral infection. Acute infection with Mononegavirales, such as Sendai viruses (SeVs), can give rise to viruses capable of persistent infection. SeVs establish persistent infection through generating copyback-type defective interfering (cbDI) genomes or acquiring temperature-sensitive mutations. Herein, we identify novel mutations associated with persistent infection and recombinant SeV mutants capable of persistent infection and autonomous production at physiological body temperature, independent of cbDI genomes or temperature-sensitive mutations. Diverse SeV populations were generated by passing the cDNA-recovered SeV Z strain 19 times through embryonated chicken eggs and subsequently infecting LLC-MK2 cells with the SeV populations to finally obtain SeV mutants capable of persistent infection and autonomous production in several types of cultured cells. Sequence analysis identified 4 or 5 mutations in the genome of the persistently infectious SeVs, distinguishing them from other existing strains with persistent infection. Recombinant SeVs carrying 4 or 5 mutations in the Z strain genome (designated SeV-Zpi or SeV-Zpi2, respectively) exhibited persistent infection and autonomous production in LLC-MK2, BHK-21, and Neuro2a cells at 37°C. SeV-Zpi and SeV-Zpi2 consistently produced viral particles even after long-term passages without cbDI particles or temperature-sensitive phenotypes. These results highlight the ability of acute infections of SeVs to spontaneously acquire mutations during replication, thereby endowing persistent infection and autonomous production at body temperature. The vectorization of SeV-Zpi and SeV-Zpi2 will contribute to both basic research and medical applications.
• Differential second messenger signaling via dopamine neurons bidirectionally regulates memory retention.
  Mai Takakura; Yu Hong Lam; Reiko Nakagawa; Man Yung Ng; Xinyue Hu; Priyanshu Bhargava; Abdalla G Alia; Yuzhe Gu; Zigao Wang; Takeshi Ota; Yoko Kimura; Nao Morimoto; Fumitaka Osakada; Ah Young Lee; Danny Leung; Tomoyuki Miyashita; Juan Du; Hiroyuki Okuno; Yukinori Hirano
  Proceedings of the National Academy of Sciences of the United States of America, 120, 36, e2304851120, 2023年08月, ［国際誌］
  英語, 研究論文（学術雑誌）, Memory formation and forgetting unnecessary memory must be balanced for adaptive animal behavior. While cyclic AMP (cAMP) signaling via dopamine neurons induces memory formation, here we report that cyclic guanine monophosphate (cGMP) signaling via dopamine neurons launches forgetting of unconsolidated memory in Drosophila. Genetic screening and proteomic analyses showed that neural activation induces the complex formation of a histone H3K9 demethylase, Kdm4B, and a GMP synthetase, Bur, which is necessary and sufficient for forgetting unconsolidated memory. Kdm4B/Bur is activated by phosphorylation through NO-dependent cGMP signaling via dopamine neurons, inducing gene expression, including kek2 encoding a presynaptic protein. Accordingly, Kdm4B/Bur activation induced presynaptic changes. Our data demonstrate a link between cGMP signaling and synapses via gene expression in forgetting, suggesting that the opposing functions of memory are orchestrated by distinct signaling via dopamine neurons, which affects synaptic integrity and thus balances animal behavior.
• Cell type‐ and layer‐specific convergence in core and shell neurons of the dorsal lateral geniculate nucleus
  Sayumi Okigawa; Masahiro Yamaguchi; Kei N. Ito; Ryosuke F. Takeuchi; Nao Morimoto; Fumitaka Osakada
  Journal of Comparative Neurology, 529, 8, 2099, 2124, Wiley, 2021年06月
  研究論文（学術雑誌）
• Efficient and robust induction of retinal pigment epithelium cells by tankyrase inhibition regardless of the differentiation propensity of human induced pluripotent stem cells.
  Arisa Ito; Ke Ye; Masanari Onda; Nao Morimoto; Fumitaka Osakada
  Biochemical and biophysical research communications, 552, 66, 72, 2021年03月17日, ［国際誌］
  英語, 研究論文（学術雑誌）, Transplantation of retinal pigment epithelium (RPE) cells derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs) hold great promise as a new therapeutic modality for age-related macular degeneration and Stargardt disease. The development of hESC/hiPSC-derived RPE cells as cell-based therapeutic products requires a robust, scalable production for every hiPSC line congruent for patients. However, individual hESC/hiPSC lines show bias in differentiation. Here we report an efficient, robust method that induces RPE cells regardless of the differentiation propensity of the hiPSC lines. Application of the tankyrase inhibitor IWR-1-endo, which potentially inhibits Wnt signaling, promoted retinal differentiation in dissociated hiPSCs under feeder-free, two-dimensional culture conditions. The other tankyrase inhibitor, XAV939, also promoted retinal differentiation. However, Wnt signaling inhibitors, IWP-2 and iCRT3, that target porcupine and β-catenin/TCF, respectively, did not. Further treatment with the GSK3β inhibitor CHIR99021 and FGF receptor inhibitor SU5402 induced hexagonal pigmented cells with phagocytotic ability. Notably, the IWR-1-endo-based differentiation method induced RPE cells even in an hiPSC line that expresses a lower level of the differentiation propensity marker SALL3, which is indicative of resistance to ectoderm differentiation. The present study demonstrated that tankyrase inhibitors cause efficient and robust RPE differentiation, irrespective of the SALL3 expression levels in hiPSC lines. This differentiation method will resolve line-to-line variations of hiPSCs in RPE production and facilitate clinical application and industrialization of RPE cell products for regenerative medicine.
• Temporally multiplexed dual-plane imaging of neural activity with four-dimensional precision
  Masanari Onda; Ryosuke F. Takeuchi; Keisuke Isobe; Toshiaki Suzuki; Yuji Masaki; Nao Morimoto; Fumitaka Osakada
  Neuroscience Research, Elsevier BV, 2021年02月
  研究論文（学術雑誌）
• Reproducible production and image-based quality evaluation of retinal pigment epithelium sheets from human induced pluripotent stem cells.
  Ke Ye; Yuto Takemoto; Arisa Ito; Masanari Onda; Nao Morimoto; Michiko Mandai; Masayo Takahashi; Ryuji Kato; Fumitaka Osakada
  Scientific reports, 10, 1, 14387, 14387, 2020年09月01日, ［国際誌］
  英語, 研究論文（学術雑誌）, Transplantation of retinal pigment epithelial (RPE) sheets derived from human induced pluripotent cells (hiPSC) is a promising cell therapy for RPE degeneration, such as in age-related macular degeneration. Current RPE replacement therapies, however, face major challenges. They require a tedious manual process of selecting differentiated RPE from hiPSC-derived cells, and despite wide variation in quality of RPE sheets, there exists no efficient process for distinguishing functional RPE sheets from those unsuitable for transplantation. To overcome these issues, we developed methods for the generation of RPE sheets from hiPSC, and image-based evaluation. We found that stepwise treatment with six signaling pathway inhibitors along with nicotinamide increased RPE differentiation efficiency (RPE6iN), enabling the RPE sheet generation at high purity without manual selection. Machine learning models were developed based on cellular morphological features of F-actin-labeled RPE images for predicting transepithelial electrical resistance values, an indicator of RPE sheet function. Our model was effective at identifying low-quality RPE sheets for elimination, even when using label-free images. The RPE6iN-based RPE sheet generation combined with the non-destructive image-based prediction offers a comprehensive new solution for the large-scale production of pure RPE sheets with lot-to-lot variations and should facilitate the further development of RPE replacement therapies.
• Multiplex Neural Circuit Tracing With G-Deleted Rabies Viral Vectors.
  Toshiaki Suzuki; Nao Morimoto; Akinori Akaike; Fumitaka Osakada
  Frontiers in neural circuits, 13, 77, 77, 2020年, ［査読有り］, ［国際誌］
  英語, Neural circuits interconnect to organize large-scale networks that generate perception, cognition, memory, and behavior. Information in the nervous system is processed both through parallel, independent circuits and through intermixing circuits. Analyzing the interaction between circuits is particularly indispensable for elucidating how the brain functions. Monosynaptic circuit tracing with glycoprotein (G) gene-deleted rabies viral vectors (RVΔG) comprises a powerful approach for studying the structure and function of neural circuits. Pseudotyping of RVΔG with the foreign envelope EnvA permits expression of transgenes such as fluorescent proteins, genetically-encoded sensors, or optogenetic tools in cells expressing TVA, a cognate receptor for EnvA. Trans-complementation with rabies virus glycoproteins (RV-G) enables trans-synaptic labeling of input neurons directly connected to the starter neurons expressing both TVA and RV-G. However, it remains challenging to simultaneously map neuronal connections from multiple cell populations and their interactions between intermixing circuits solely with the EnvA/TVA-mediated RV tracing system in a single animal. To overcome this limitation, here, we multiplexed RVΔG circuit tracing by optimizing distinct viral envelopes (oEnvX) and their corresponding receptors (oTVX). Based on the EnvB/TVB and EnvE/DR46-TVB systems derived from the avian sarcoma leukosis virus (ASLV), we developed optimized TVB receptors with lower or higher affinity (oTVB-L or oTVB-H) and the chimeric envelope oEnvB, as well as an optimized TVE receptor with higher affinity (oTVE-H) and its chimeric envelope oEnvE. We demonstrated independence of RVΔG infection between the oEnvA/oTVA, oEnvB/oTVB, and oEnvE/oTVE systems and in vivo proof-of-concept for multiplex circuit tracing from two distinct classes of layer 5 neurons targeting either other cortical or subcortical areas. We also successfully labeled common input of the lateral geniculate nucleus to both cortico-cortical layer 5 neurons and inhibitory neurons of the mouse V1 with multiplex RVΔG tracing. These oEnvA/oTVA, oEnvB/oTVB, and oEnvE/oTVE systems allow for differential labeling of distinct circuits to uncover the mechanisms underlying parallel processing through independent circuits and integrated processing through interaction between circuits in the brain.
• The polycomb component Ring1B regulates the timed termination of subcerebral projection neuron production during mouse neocortical development
  Nao Morimoto-Suzki; Yusuke Hirabayashi; Kelsey Tyssowski; Jun Shinga; Miguel Vidal; Haruhiko Koseki; Yukiko Gotoh
  DEVELOPMENT, 141, 22, 4343, 4353, 2014年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Polycomb Limits the Neurogenic Competence of Neural Precursor Cells to Promote Astrogenic Fate Transition
  Yusuke Hirabayashi; Nao Suzki; Masafumi Tsuboi; Takaho A. Endo; Tetsuro Toyoda; Jun Shinga; Haruhiko Koseki; Miguel Vidal; Yukiko Gotoh
  NEURON, 63, 5, 600, 613, 2009年09月, ［査読有り］
  英語, 研究論文（学術雑誌）

• 胚性幹細胞由来オルガノイド複合体を用いたin vitro非ヒト霊長類脳モデルの構築
  小寺知輝; 原大樹; 森本菜央; 竹内遼介; 小坂田文隆; 小坂田文隆; 小坂田文隆; 小坂田文隆, 日本神経化学会大会抄録集(Web), 65th, 2022年
• 低毒化G欠損狂犬病ウイルスベクターの開発
  山口真広; 恩田将成; 正木佑治; 竹内遼介; 森本菜央; 小坂田文隆; 小坂田文隆, 日本薬理学雑誌, 156, Supplement, 2021年
• ヒトiPS細胞由来網膜色素上皮細胞のシート作製とその評価
  葉珂; 伊藤ありさ; 恩田将成; 竹内遼介; 森本菜央; 森本菜央; 小坂田文隆; 小坂田文隆; 小坂田文隆, 日本薬理学雑誌, 154, Supplement, 2019年
• 狂犬病ウイルスベクターを用いた神経回路解析法
  山口 真広; 森本 菜央; 小坂田 文隆, バイオイノベーションに向けて ～バイオテクノロジーの新技術からの新しい視点～, 237, 246, 2019年
• (Tsukahara Award) Temporal regulation of neural stem cell fate in the developing mouse neocortex
  Yusuke Hirabayashi; Nao Suzki; Yukiko Gotoh, NEUROSCIENCE RESEARCH, 68, E3, E3, 2010年
  英語, 研究発表ペーパー・要旨（国際会議）

• 小胞体ストレスに応答した小胞体膜局在タンパク質の膜トポロジー反転現象の発見とその制御機構の解明
  森本菜央; 山田珠鈴; 岡崎朋彦
  第62回日本生化学会北海道支部例会, 2025年07月14日
  ［招待講演］
• セロトニン作動性ニューロンがショウジョウバエ聴覚応答の行動 時間を調節する
  森本菜央,、恩田将成、石田彩乃、竹内遼介、磯部圭佑、上川内あづさ、小坂 田文隆
  第43回日本神経科学大会, 2020年07月
  ［招待講演］

• 日本神経科学学会

• ショウジョウバエ内部状態に依存したリズミックな神経活動の分子基盤の解明
  科学研究費助成事業
  2021年04月01日 - 2024年03月31日
  森本 菜央; 小坂田 文隆
  動物には、環境からの情報を統合するため、脳内に情報を一時的に保存する機構が備わっている。情報の一時的な保存は、外的刺激に依存しない神経活動により担われると考えられる。 このような活動をする神経細胞はリズミックな神経活動を行うことが明らかになってきてはいるが、リズム生成の分子機構の詳細は未解明である。本研究は、ショウジョウバエ脳内にて、申請者が神経活動イメージングの際に見出した「求愛刺激により誘導されたリズミックな神経活動が刺激終了後も持続する」活動パターンをとる神経細胞に着目する。この細胞を含む神経回路を単一細胞レベルで特定し、リズミックな神経活動が神経回路や動物の行動に与える摂動を明らかにすることで、リズミックな神経活動を生成する分子機構を解明し、その生理的意義を理解することを目的とする。
  当該年度においては、リズム生成に必要な分子を探るため、まず、着目したポタシウムイオンチャネルの阻害剤を用いて、刺激誘導性のリズムがどう変化するかをカルシウムイメージングにて調べた。その結果、阻害剤添加群ではリズムの時間周波数が小さくなった。このことから、このポタシウムイオンチャネルがリズムの時間周波数の決定に重要であることが示唆された。
  現在、このチャネル、および時間周波数が行動にどのように影響を与えるかと調べるため、ポタシウムチャネルを詐害したときの、ショウジョウバエの応答行動を行動実験で検証している。
  日本学術振興会, 基盤研究(C), 北海道大学, 21K06372
• ショウジョウバエを用いた、セロトニンによる時間経過に伴う価値判断システムの解析
  科学研究費助成事業
  2019年04月01日 - 2022年03月31日
  森本 菜央
  動物は、環境から受け取る情報に対し、価値判断を行い、情報への応答行動を調節していると考えられるが、その神経機構はほとんど未解明であった。本研究課題では、研究代表者がショウジョウバエの聴覚応答行動の系にて独自に見出した、応答行動の量や時間の調節にセロトニンが関与するという予備的な知見をもとにして、セロトニン作動性細胞集団およびその作用点細胞を同定することに成功した。これにより、出力行動を調節するセロトニン神経回路の一端を明らかになった。
  日本学術振興会, 若手研究, 19K16257
• ショウジョウバエ求愛行動をモデルにした馴化調節を担う神経機構の解明
  科学研究費助成事業
  2016年04月01日 - 2018年03月31日
  森本 菜央; 上川内 あづさ; 小坂田 文隆
  動物は無益・無害な刺激に長時間、暴露されると、刺激への反応を低下させる。これが馴化（慣れ）である。しかし、刺激が有益・有害である場合、動物は繰り返される刺激に応答し続けなければならない。このような、刺激への価値判断に応じて、馴化レベルが調節される神経メカニズムはほとんど未解明であった。本研究ではショウジョウバエの求愛行動において申請者が独自に確立した系をモデルとし、価値判断システムにより馴化レベルが調節される神経細胞群の一部を同定することに成功した。
  日本学術振興会, 若手研究(B), 名古屋大学, 16K18362