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Clarification of the cell-quality-control systems eliminating unhealthy cells from embryonic tissue and their dysregulation

Research Project

Project/Area Number 20K21502
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 48:Biomedical structure and function and related fields
Research InstitutionOsaka University

Principal Investigator

Ishitani Tohru  大阪大学, 微生物病研究所, 教授 (40448428)

Project Period (FY) 2020-07-30 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2021: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2020: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Keywordsモザイク疾患 / 不良細胞 / ゼブラフィッシュ
Outline of Research at the Start

近年、ヒト胚では発生初期からランダムな遺伝子変異が頻繁に起きており、その変異により生じるモザイクが先天性疾患に関わることが明らかにされた。しかし、発生期に生じた変異がどのようなプロセスを経て疾患を引き起こすのかは不明である。一方で我々は最近、胚が変異細胞を除去するシステムを有することを発見しており、このシステムが変異モザイクの出現を抑制し、疾患を予防する能力があると推測している。そこで本研究では、モザイク疾患モデルゼブラフィッシュを作製・解析することでモザイク疾患と変異細胞除去機構の関係と、モザイク疾患の発症プロセスを分子・細胞・個体レベルで解明する。

Outline of Final Research Achievements

We aimed to elucidate the relationship between mosaic disease and cell-quality-control system using zebrafish as a model. We succeeded to reveal that, in zebrafish larvae, neighboring normal cells sense precancerous cells and then induce senescence and physically push out these precancerous cells. In addition, in epithelia with p53 mutations or DNA damage, precancerous cells survive without being eliminated, and induce proliferation or secondary cellular senescence in adjacent normal cells to induce primary tumors.Thus,
we have clarified a new mechanism by which neighboring cells sense and eliminate defective cells during development. Furthermore, we have clarified that additional mutations and environmental factors suppress this elimination mechanism and drive disease development. Our results would provide a new understanding of the pathogenesis of human diseases.

Academic Significance and Societal Importance of the Research Achievements

ゼブラフィッシュを用いたイメージング解析により、新たな疾患発症機構を明らかにした。これは、発生学のみならず医学においても重要な発見である。また、近年、動物愛護の考え方から哺乳類モデルを使った制限が徐々に制限され始めているが、本成果は非哺乳類モデルの医学研究における有用性を示す重要な成果と言える。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (39 results)

All 2022 2021 2020 Other

All Journal Article (13 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 13 results,  Open Access: 10 results) Presentation (21 results) (of which Int'l Joint Research: 1 results,  Invited: 10 results) Book (4 results) Remarks (1 results)

  • [Journal Article] Extracellular ATP facilitates cell extrusion from epithelial layers mediated by cell competition or apoptosis2022

    • Author(s)
      Mori Yusuke、Shiratsuchi Naoka、Sato Nanami、Chaya Azusa、Tanimura Nobuyuki、Ishikawa Susumu、Kato Mugihiko、Kameda Ikumi、Kon Shunsuke、Haraoka Yukinari、Ishitani Tohru、Fujita Yasuyuki
    • Journal Title

      Current Biology

      Volume: 32 Issue: 10 Pages: 2144-2159.e5

    • DOI

      10.1016/j.cub.2022.03.057

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] De novo non-synonymous CTR9 variants are associated with motor delay and macrocephaly: human genetic and zebrafish experimental evidence2022

    • Author(s)
      Suzuki Hisato、Aoki Kana、Kurosawa Kenji、Imagawa Kazuo、Ohto Tatsuyuki、Yamada Mamiko、Takenouchi Toshiki、Kosaki Kenjiro、Ishitani Tohru
    • Journal Title

      Human Molecular Genetics

      Volume: 31 Issue: 22 Pages: 3846-3854

    • DOI

      10.1093/hmg/ddac136

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rapid reverse genetics systems for Nothobranchius furzeri, a suitable model organism to study vertebrate aging2022

    • Author(s)
      Oginuma Masayuki、Nishida Moana、Ohmura-Adachi Tomomi、Abe Kota、Ogamino Shohei、Mogi Chihiro、Matsui Hideaki、Ishitani Tohru
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 11628-11628

    • DOI

      10.1038/s41598-022-15972-3

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Calcium sparks enhance the tissue fluidity within epithelial layers and promote apical extrusion of transformed cells2022

    • Author(s)
      Kuromiya K, Aoki K, Ishibashi K, Yotabun M, Sekai M, Tanimura N, Iijima S, Ishikawa S, Kamasaki T, Akieda Y, Ishitani T, Hayashi T, Toda S, Yokoyama K, Lee CG, Usami I, Inoue H, Takigawa I, Gauquelin E, Sugimura K, Hino N, Fujita Y
    • Journal Title

      Cell Reports

      Volume: 40 Issue: 2 Pages: 111078-111078

    • DOI

      10.1016/j.celrep.2022.111078

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis2022

    • Author(s)
      Haraoka Yukinari、Akieda Yuki、Nagai Yuri、Mogi Chihiro、Ishitani Tohru
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 1-15

    • DOI

      10.1038/s41467-022-29061-6

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel role for PRL in regulating epithelial cell density by inducing apoptosis at confluence2022

    • Author(s)
      Lohani Sweksha、Funato Yosuke、Akieda Yuki、Mizutani Kiyohito、Takai Yoshimi、Ishitani Tohru、Miki Hiroaki
    • Journal Title

      Journal of Cell Science

      Volume: 135 Issue: 2 Pages: 1-14

    • DOI

      10.1242/jcs.258550

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish.2021

    • Author(s)
      Inoue M, Miyahara H, Shiraishi H, Shimizu N, Tsumori M, Kiyota K, Maeda M, Umeda R, Ishitani T, Hanada R, Ihara K, Hanada T.
    • Journal Title

      Sci Rep

      Volume: 11 Issue: 1 Pages: 8392-8392

    • DOI

      10.1038/s41598-021-87879-4

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Biallelic CDK9 variants as a cause of a new multiple-malformation syndrome with retinal dystrophy mimicking the CHARGE syndrome2021

    • Author(s)
      Nishina Sachiko、Hosono Katsuhiro、Ishitani Shizuka、Kosaki Kenjiro、Yokoi Tadashi、Yoshida Tomoyo、Tomita Kaoru、Fukami Maki、Saitsu Hirotomo、Ogata Tsutomu、Ishitani Tohru、Hotta Yoshihiro、Azuma Noriyuki
    • Journal Title

      Journal of Human Genetics

      Volume: - Issue: 10 Pages: 1021-1027

    • DOI

      10.1038/s10038-021-00909-x

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.2021

    • Author(s)
      Zarate YA, Uehara T, Kaname T, Ishitani T, Kosaki K. et. al.
    • Journal Title

      Genet Med.

      Volume: - Issue: 6 Pages: 1050-1057

    • DOI

      10.1038/s41436-020-01091-9

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Exosc2 deficiency leads to developmental disorders by causing a nucleotide pool imbalance in zebrafish2020

    • Author(s)
      Yatsuka Hiroyuki、Hada Kazumasa、Shiraishi Hiroshi、Umeda Ryohei、Morisaki Ikuko、Urushibata Hirotaro、Shimizu Nobuyuki、Sebastian Wulan Apridita、Hikida Takatoshi、Ishitani Tohru、Hanada Reiko、Shimada Tatsuo、Kimoto Kenichi、Kubota Toshiaki、Hanada Toshikatsu
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 533 Issue: 4 Pages: 1470-1476

    • DOI

      10.1016/j.bbrc.2020.10.044

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons.2020

    • Author(s)
      Akamine S, Okuzono S, Yamamoto H, Setoyama D, Sagata N, Ohgidani M, Kato TA, Ishitani T, Kato H, Masuda K, Matsushita Y, Ono H, Ishizaki Y, Sanefuji M, Saitsu H, Matsumoto N, Kang D, Kanba S, Nakabeppu Y, Sakai Y, Ohga S.
    • Journal Title

      FASEB J

      Volume: 34 Issue: 12 Pages: 16601-16621

    • DOI

      10.1096/fj.202001113r

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants2020

    • Author(s)
      Tomoko Uehara, Kota Abe, Masayuki Oginuma, Shizuka Ishitani, Hiroshi Yoshihashi, Nobuhiko Okamoto, Toshiki Takenouchi, Kenjiro Kosaki, Tohru Ishitani
    • Journal Title

      Scientific reports

      Volume: 10 Issue: 1 Pages: 1-7

    • DOI

      10.1038/s41598-020-74642-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tyrosine pre-transfer RNA fragments are linked to p53-dependent neuronal cell death via PKM22020

    • Author(s)
      Inoue Masanori、Hada Kazumasa、Shiraishi Hiroshi、Yatsuka Hiroyuki、Fujinami Hiroyuki、Morisaki Ikuko、Nishida Yoshihiro、Matsubara Etsuro、Ishitani Tohru、Hanada Reiko、Matsumoto Masaki、Penninger Josef M.、Ihara Kenji、Hanada Toshikatsu
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: May 3 Issue: 3 Pages: 155-163

    • DOI

      10.1016/j.bbrc.2020.02.157

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 魚が切り拓くヒト疾患・老化研究2022

    • Author(s)
      石谷 太
    • Organizer
      Cardiovascular- Metabolism-Aging Research Seminar (MARS)
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 魚が切り拓くヒト疾患・老化研究2022

    • Author(s)
      石谷 太
    • Organizer
      令和4年度日本生化学会 九州支部例会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] TLR/NFκB-mediated indirect negative feedback regulation of Wnt/β-catenin signaling controls precise size of zebrafish dorsal organizer.2022

    • Author(s)
      Zou Juqi、石谷 太
    • Organizer
      the 17th International Zebrafish Conference, plenary session
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] p53追加変異は細胞老化を介したがん原細胞排除を破綻させ初期腫瘍形成を促進する2022

    • Author(s)
      原岡由喜也、龝枝佑紀、石谷 太
    • Organizer
      第74回 日本細胞生物学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 空間トランスクリプトーム技術を用いた細胞競合のメカニズム解析2022

    • Author(s)
      三宅 舞、龝枝 佑紀、原岡 由喜也、原田 哲仁、大川 恭行、石谷 太
    • Organizer
      第74回 日本細胞生物学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 細胞間張力の局所的変化に注目した細胞競合の起動原理の解析2022

    • Author(s)
      青木佳南、石谷 太
    • Organizer
      第74回日本細胞生物学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 細胞競合は器官構築過程におけるモルフォゲン勾配の自己修復を支える2022

    • Author(s)
      松本かな子、龝枝 佑紀、石谷 太
    • Organizer
      第74回日本細胞生物学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] モルフォゲン勾配のロバストネスの分子基盤を細胞競合から理解する2021

    • Author(s)
      松本かな子、龝枝佑紀、石谷 太
    • Organizer
      日本細胞生物学会ワークショップ
    • Related Report
      2021 Research-status Report
  • [Presentation] 環境要因による胚の細胞品質管理機構の破綻と成体におけるモザイク関連疾患の理解2021

    • Author(s)
      石谷太
    • Organizer
      第61回日本先天異常学会学術集会シンポジウム
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Additional TP53 mutation switches oncogene-induced senescence from suppressor to driver in primary tumorigenesis.2021

    • Author(s)
      原岡由喜也、龝枝佑紀、石谷 太
    • Organizer
      第80回日本癌学会学術総会シンポジウム
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 小型魚類ゼブラフィッシュの特性を活かしてヒト先天性疾患の発症メカニズムに迫る2021

    • Author(s)
      石谷 太
    • Organizer
      日本人類遺伝学会第66回大会 第28回日本遺伝子診療学会大会 合同開催シンポジウム
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Wntモルフォゲン勾配を利用した不良細胞感知・排除機構2021

    • Author(s)
      石谷 太
    • Organizer
      第94回日本生化学会大会 シンポジウム
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Cell competition contributes to the autonomous error correction of morphogen gradient.2021

    • Author(s)
      石谷 太
    • Organizer
      第44回日本分子生物学会年会シンポジウム
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] モルフォゲン勾配のロバストネスの分子基盤を細胞競合から理解する2021

    • Author(s)
      松本かな子、龝枝佑紀、石谷 太
    • Organizer
      日本分子生物学会年会ワークショップ
    • Related Report
      2021 Research-status Report
  • [Presentation] モルフォゲン勾配のロバストネスの分子基盤を細胞競合から理解する2021

    • Author(s)
      松本かな子、龝枝佑紀、石谷 太
    • Organizer
      日本分子生物学会年会ポスター
    • Related Report
      2021 Research-status Report
  • [Presentation] がん原細胞-隣接細胞間の競合的・協調的コミュニケーションを小型魚類イメージングで解き明かす2021

    • Author(s)
      原岡由喜也、龝枝佑紀、石谷 太
    • Organizer
      日本分子生物学会年会ポスター
    • Related Report
      2021 Research-status Report
  • [Presentation] Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis2021

    • Author(s)
      原岡由喜也、龝枝佑紀、石谷 太
    • Organizer
      6th ICSA
    • Related Report
      2021 Research-status Report
  • [Presentation] Cell-cell communication-mediated error correcting mechanism of Wnt morphogen gradient2021

    • Author(s)
      龝枝 佑紀、小神野 翔平、石谷 太
    • Organizer
      Wnt研究会2021
    • Related Report
      2020 Research-status Report
  • [Presentation] 魚が切り拓くヒト疾患・老化研究2021

    • Author(s)
      石谷 太
    • Organizer
      日本循環器学会 meet the expert
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 細胞競合が支える発生ロバストネス2020

    • Author(s)
      石谷太
    • Organizer
      炎症再生医学会シンポジウム
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 細胞競合によるエラー修復は脊椎動物の発生と組織恒常性を支える2020

    • Author(s)
      石谷太
    • Organizer
      日本分子生物学会年会シンポジウム
    • Related Report
      2020 Research-status Report
    • Invited
  • [Book] 遺伝子医学・40号 小型魚類ゼブラフィッシュの特性を活かしてヒト疾患の発症メカニズムに迫る2022

    • Author(s)
      石谷 太
    • Total Pages
      7
    • Publisher
      メディカル・ドゥ
    • ISBN
      9784909508188
    • Related Report
      2022 Annual Research Report
  • [Book] 遺伝子医学40号 IRUD-Beyond:小型モデル生物および患者iPS細胞を 用いた希少・未診断疾患へのアプローチ2022

    • Author(s)
      石谷太(分担執筆)
    • Total Pages
      7
    • Publisher
      メディカルドゥ
    • ISBN
      9784909508188
    • Related Report
      2021 Research-status Report
  • [Book] 月刊細胞「細胞の個性と競合」・53巻2021

    • Author(s)
      石谷太(分担執筆)
    • Total Pages
      4
    • Publisher
      ニューサイエンス社
    • Related Report
      2021 Research-status Report
  • [Book] 医学のあゆみ 細胞競合による生体制御とがん ; 生理的な細胞競合2020

    • Author(s)
      龝枝佑紀、石谷太(分担執筆)
    • Total Pages
      7
    • Publisher
      医歯薬出版
    • Related Report
      2020 Research-status Report
  • [Remarks] 石谷研究室HP

    • URL

      https://ishitani-lab.biken.osaka-u.ac.jp/

    • Related Report
      2022 Annual Research Report 2021 Research-status Report 2020 Research-status Report

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Published: 2020-08-03   Modified: 2024-01-30  

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