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Expression characteristics of Sez12 gene, the murine homolog of DGCR2, in chondrocytes from 22q11.2 deletion syndrome model with knocked-in GFP

Research Project

Project/Area Number 19K10062
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 57010:Oral biological science-related
Research InstitutionTokai University

Principal Investigator

KAJIWARA Kagemasa  東海大学, 医学部, 客員講師 (00204397)

Co-Investigator(Kenkyū-buntansha) 木村 穣  東海大学, 総合医学研究所, 特任教授 (10146706)
内堀 雅博  東海大学, 医学部, 助教 (50749273)
太田 嘉英  東海大学, 医学部, 教授 (60233152)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords22q11.2欠失症候群 / DGCR2 / Sez12 / Df1 / GFPノックイン / 肥大軟骨細胞 / 頭蓋底軟骨結合 / TGF-betaシグナル / DGCR2遺伝子 / ノックアウトマウス / GFPノックインマウス / TGF-beta / Df1マウス / GFP / Tbx1 / Dgcr2
Outline of Research at the Start

DGCR2は22q11.2欠失症候群のゲノム欠失領域に位置する遺伝子である。そのマウス相同遺伝子Sez12のノックアウトマウスは22q11.2欠失症候群と類似した顎顔面異常を示し、軟骨細胞の成長不良で頭蓋底軟骨結合が早期に消失する。Sez12ノックアウト軟骨細胞ではTGF-betaシグナルが亢進し、Sez12による TGF-betaシグナル制御が予想された。そこでSez12欠失による各種増殖分化シグナルの変化を軟骨細胞・マウス個体で検討する。またDGCR2多型の変異をヒト培養細胞で再現し、TGF-betaシグナルへの影響を検討し、DGCR2変異と顎顔面骨格成長との関連性を追求する。

Outline of Final Research Achievements

To explore the DGCR2 gene function, we generated Sez12 (the mouse homolog of DGCR2) -knockout/GFP-knocked-in mice, which showed maxillofacial hypoplasia caused by early malformations of basilar cartilage and differentiation defects of pre-hypertrophic chondrocytes. In the homozygous Sez12-KO chondrocytes treated with TGF-beta, we found significant activation of TGF-beta signaling and decrease of chondrocytes with expression of type X collagen, compared to wild-type ones showing expression of both type II and type X collagen. Furthermore, the primary chondrocytes with heterozygous mutants from both Sez12-KO and Df1 region which is heterozygously deleted a large portion of mouse genome corresponding to human 22q11.2 showed similar maxillofacial phenotypes and knocked-in GFP expression. These results suggest that DGCR2 together with other gene(s) in 22q11.2 could regulate the TGF-beta signaling activity for differentiation from replicative chondrocytes to hypertrophic ones after birth.

Academic Significance and Societal Importance of the Research Achievements

本研究は、ヒト染色体22番長腕11.2領域の欠失により引き起こされる顔貌異常の発症メカニズム解明のため、欠失ゲノム領域の遺伝子機能を検討し、22q11.2欠失症候群の顔貌骨格異常の根本的治療の基盤となった。本研究で解析されたDGCR2遺伝子は、22q11.2欠失領域のいくつかの遺伝子と協調して頭蓋底の軟骨内骨化に寄与している。特記すべきことは、DGCR2欠失マウスが生後若齢で顔貌異常を認めることである。つまり、本疾患のみならず、他の原因による顔面骨格異常であっても、DGCR2を標的とした出生後の活性調節治療で症状が改善できる可能性が示唆され、外科治療に依存しない出生後治療に期待がもてる。

Report

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

    (17 results)

All 2021 2020 2019 Other

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (9 results) (of which Int'l Joint Research: 2 results) Remarks (3 results)

  • [Journal Article] Administration of astragalus membranaceus prevented cisplatin-induced AKI, especially in old mice2021

    • Author(s)
      Kajiwara Kagemasa、Arai Makoto、Nogami Tatsuya、Nakada Yoshinobu、Nagashima Go、Tashiro Kyoka、Kinue Takaaki
    • Journal Title

      Nephrology Dialysis Transplantation

      Volume: 36 Issue: Supplement_1

    • DOI

      10.1093/ndt/gfab084.0015

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Analysis of treatment with Astragalus membranaceus powder in patients with chronic kidney disease2021

    • Author(s)
      Makoto Arai, Tatsuya Nogami, Izumi Aoyama, Kagemasa Kajiwara, Saki Manabe, Hideki Ozawa
    • Journal Title

      International Medical Journal

      Volume: 28 Pages: 328-330

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A large intermediate domain of vertebrate REV3 protein is dispensable for ultraviolet-induced translesion replication2021

    • Author(s)
      Jun Takezawa, Anna Shimazaki, Hidemi Takimoto, Kagemasa Kajiwara, and Kouichi Yamada
    • Journal Title

      DNA repair

      Volume: 98 Pages: 103031-103039

    • DOI

      10.1016/j.dnarep.2020.103031

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression of CNDP1 protein is regulated by age-dependent and AKI-related Astragalus membranaceous effects in mice2020

    • Author(s)
      Kagemasa Kajiwara, Makoto Arai, Yoshinobu Nakada, Go Nagashima, and Takaaki Kinoue
    • Journal Title

      Nephrology Dialysis Transplantation

      Volume: 35 Issue: Supplement_3

    • DOI

      10.1093/ndt/gfaa142.p0552

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Administration of Astragalus Membranaceus prevented kidney dysfunction in cisplatin-AKI model mice2019

    • Author(s)
      Kagemasa Kajiwara, Arai Makoto, Nakada Yoshinobu, Kinoue Takaaki
    • Journal Title

      Nephrology Dialysis Transplantation

      Volume: 34 Issue: Supplement_1

    • DOI

      10.1093/ndt/gfz106.fp292

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Administration of astragalus membranaceus prevented cisplatin-induced AKI, especially in old mice2021

    • Author(s)
      Kajiwara Kagemasa、Arai Makoto、Nogami Tatsuya、Nakada Yoshinobu、Nagashima Go、Tashiro Kyoka、Kinue Takaaki
    • Organizer
      European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 22q11.2欠失症候群モデルの初代軟骨細胞におけるヘテロ型DGCR2遺伝子の発現解析2021

    • Author(s)
      梶原景正
    • Organizer
      第63回歯科基礎医学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 線虫寿命モデルの遺伝子発現解析を用いたダイオウ薬効に関わるヒト分子メカニズム2021

    • Author(s)
      江口智美、田代杏夏、長島豪、新井信、梶原景正
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 線虫寿命モデルの遺伝子発現解析を用いたダイオウ薬効に関わるヒト分子メカニズム の解明2021

    • Author(s)
      田代杏夏、江口智美、長島豪、新井信、梶原景正
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 22q11.2欠失症候群の顎顔面症状におけるヘテロDGCR2遺伝子欠失の役割2020

    • Author(s)
      梶原 景正, 長島豪, 田代 杏夏, 内堀 雅博, 太田 嘉英
    • Organizer
      第93回 日本生化学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Expression of CNDP1 protein is regulated by age-dependent and AKI-related Astragalus membranaceous effects in mice2020

    • Author(s)
      Kagemasa Kajiwara, Makoto Arai, Yoshinobu Nakada, Go Nagashima, Takaaki Kinoue
    • Organizer
      the 57th ERA-EDTA Virtual Congress
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Dgcr2ノックアウトマウスを用いた22q11.2欠失症候群の顎顔面症状と頭蓋底成長との関連性の解析2019

    • Author(s)
      梶原 景正
    • Organizer
      第61回歯科基礎医学会学術大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 22q11.2欠失症候群て欠失する DGCR2遺伝子は軟骨細胞分化過程でTGF-betaシクグナルを抑制性に制御する2019

    • Author(s)
      梶原 景正, 長島 豪
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 動物細胞DNAポリメラーゼζ(REV3)の長大な中間領域は損傷乗り越え複製(TLS)に必須ではない?2019

    • Author(s)
      山田 晃一, 竹澤 純, 嶋崎 杏奈, 梶原 景正
    • Organizer
      第25回 DNA複製・組換え・修復ワークショップ
    • Related Report
      2019 Research-status Report
  • [Remarks] Kajiwara K. Research Unit

    • URL

      http://kage.med.u-tokai.ac.jp/

    • Related Report
      2021 Annual Research Report
  • [Remarks] Kajiwara, K. Research Unit

    • URL

      http://kage.med.u-tokai.ac.jp/

    • Related Report
      2020 Research-status Report
  • [Remarks] http://kage.med.u-tokai.ac.jp/

    • Related Report
      2019 Research-status Report

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

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