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Ventricular transcription factor cascade in the formation of atrioventricular valve and septum during embryonic heart development.

Research Project

Project/Area Number 19K17318
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionJikei University School of Medicine (2020-2021)
National Cardiovascular Center Research Institute (2019)

Principal Investigator

Seya Daiki  東京慈恵会医科大学, 医学部, ポストドクトラルフェロー (30806021)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Keywords先天性心疾患 / 転写調節因子 / 発現制御 / ノックアウトマウス / 形態形成 / 発生・分化 / 心血管系 / 発生・形態形成
Outline of Research at the Start

先天性心疾患は様々な種類の性質の異なる細胞群の増殖・移動・極性などを制御する分子機構が障害されるために発症する。そのため心臓形態形成過程における心臓の各領域での遺伝子群の発現・機能、そして構成細胞の時空間的な動態を知ることは、先天性心疾患の発症機序を理解する上で非常に重要である。本申請研究では、Hey2転写調節因子の領域特異的欠失マウスにおける組織学的な解析とHey2の上流・下流転写因子カスケードの研究を通して、正常心臓形態形成機構とHey2欠失により生ずる三尖弁・右心室・心室中隔形態異常のメカニズムを解明する。

Outline of Final Research Achievements

This study aims to elucidate the significance of Hey2 and the upstream/downstream transcription factor cascade in cardiac morphogenesis and the mechanisms of morphological abnormalities, such as ventricular septal defect, dysplastic tricuspid valve and hypoplastic right ventricle, caused by the Hey2 gene deletion. We generated Hey2 conditional knockout (cKO) mice specific to the myocardium of the right ventricle and ventricular septum using the Mef2c-AHF-Cre mouse strain and demonstrated that Hey2 played an important role in right ventricular development, at least in part, through mitigating the Tbx2-dependent inhibition of Mycn expression. In the analyses of the upstream transcriptional regulation of Hey2 expression, we identified a distal Hey2 enhancer that was activated by Gata and Tbx20 and was essential for Hey2 expression in the ventricular myocardium.

Academic Significance and Societal Importance of the Research Achievements

先天性心疾患は新生児の1%に認められる発症頻度の高い疾患であり、胎生期心臓形成の分子基盤を明らかにすることは、その病因究明や、新規治療薬の開発につながる重要な課題である。Hey2 KOマウスで観察される心臓形態異常(心室中隔欠損、三尖弁閉鎖および右心室低形成)は、ヒト先天性心疾患にも認める典型的な構造異常であり、本研究成果は、これらの疾患の病因として右心室心筋での遺伝子発現の調節異常が関与していることを強く示唆するものである。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (8 results)

All 2022 2021 2020 2019

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (4 results)

  • [Journal Article] Sample Preparation for Computed Tomography-based Three-dimensional Visualization of Murine Hind-limb Vessels2021

    • Author(s)
      Seya Daiki、Xu Yuqing、Mukunoki Toshifumi、Tsujita Kenichi、Nakagawa Osamu、Arima Yuichiro
    • Journal Title

      Journal of visualized experiments : JoVE

      Volume: - Issue: 176

    • DOI

      10.3791/63009

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A role of Hey2 transcription factor for right ventricle development through regulation of Tbx2-Mycn pathway during cardiac morphogenesis2021

    • Author(s)
      Seya Daiki、Ihara Dai、Shirai Manabu、Kawamura Teruhisa、Watanabe Yusuke、Nakagawa Osamu
    • Journal Title

      Development, Growth & Differentiation

      Volume: 63 Issue: 1 Pages: 82-92

    • DOI

      10.1111/dgd.12707

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Importance of endothelial Hey1 expression for thoracic great vessel development and its distal enhancer for Notch-dependent endothelial transcription2020

    • Author(s)
      Watanabe Yusuke、Seya Daiki、Ihara Dai、Ishii Shuhei、Uemoto Taiki、Kubo Atsushi、Arai Yuji、Isomoto Yoshie、Nakano Atsushi、Abe Takaya、Shigeta Mayo、Kawamura Teruhisa、Saito Yoshihiko、Ogura Toshihiko、Nakagawa Osamu
    • Journal Title

      Journal of Biological Chemistry

      Volume: 295 Issue: 51 Pages: 17632-17645

    • DOI

      10.1074/jbc.ra120.015003

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression of Hey2 transcription factor in the early embryonic ventricles is controlled through a distal enhancer by Tbx20 and Gata transcription factors2020

    • Author(s)
      Ihara Dai、Watanabe Yusuke、Seya Daiki、Arai Yuji、Isomoto Yoshie、Nakano Atsushi、Kubo Atsushi、Ogura Toshihiko、Kawamura Teruhisa、Nakagawa Osamu
    • Journal Title

      Developmental Biology

      Volume: 461 Issue: 2 Pages: 124-131

    • DOI

      10.1016/j.ydbio.2020.02.001

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Changes in the transcriptional profile of rat pulmonary veins before and after birth2022

    • Author(s)
      瀬谷大貴、赤池徹、岩瀬晃康、栗原裕基、南沢享
    • Organizer
      第99回日本生理学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 周産期におけるラット肺静脈の転写プロファイルの検討2021

    • Author(s)
      瀬谷大貴、赤池徹、南沢享
    • Organizer
      第6回日本肺高血圧・肺循環学会学術集会/第27回日本小児肺循環研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Transcriptional profiles of the rat pulmonary vein during a perinatal period2021

    • Author(s)
      瀬谷大貴、赤池徹、南沢享
    • Organizer
      第126回日本解剖学会総会・全国学術大会/第98回日本生理学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Hey2 expression in the right ventricle and interventricular septum is essential for cardiac morphogenesis2019

    • Author(s)
      瀬谷大貴、井原大、川村晃久、渡邉裕介、中川修
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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