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Analysis of Wnt signaling pathway during cardiomyocyte differentiation

Research Project

Project/Area Number 14570648
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionSHINSHU UNIVERSITY SCHOOL OF MEDICINE

Principal Investigator

IMAMURA Hiroshi  Shinshu Univ. Sch. of Med., Assistant Professor, 医学部附属病院, 助教授 (60283264)

Co-Investigator(Kenkyū-buntansha) KOMURO Issei  Chiba Univ. Grad. Sch. of Med., Professor, 大学院・医学研究院, 教授 (30260483)
YAZAKI Yoshikazu  Shinshu Univ. Sch. of Med., Assistant Professor, 医学部附属病院, 講師 (50283263)
大和 眞史  信州大学, 医学部附属病院, 助教授 (40169082)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsCardiomyocyte differentiation / Cardiomyocyte regeneration / Wnt signaling pathway / P19CL6 cell / Csx / Nkx2.5 / Nkx2.5 / 心筋分化 / 発生 / 心筋再生 / ホメオボックス / 遺伝子 / 転写因子
Research Abstract

It has been reported that Wnt-8c was expressed in the primitive streak and posterior lateral plate mesoderm during gastrulation in chick embryo and that ectopic expression of Wnt-8c in the precardiac region represses cardiac-specific gene expressions. Dkk-1, a Wnt inhibitor, induces cardiac-specific gene expressions in posterior lateral plate mesoderm where Wnt-8c was expressed, suggesting that inhibition of Wnt activity can induce ectopic expression of cardiac-specific genes and beating cardiomyocytes in nonprecardiac mesodermal cells, and that Wnt is an inhibitory signaling molecule in cardiac development. However, the precise molecular mechanisms by which Wnt regulates cardiac cell differentiation are largely unknown. In the present study, we examined the molecular mechanisms by which Wnt inhibits cardiac differentiation by using the P19CL6 in vitro cardiomyocyte differentiation system, a clonal derivative of P19 embryonal teratocarcinoma cells. We isolated two permanent P19CL6 cell lines, CL6-Xwnt-8 and CL6-hDkk-1, which constitutively overexpress Xenopus Wnt-8 and human Dkk-1, respectively. Parental P19CL6 cells differentiate into beating cardiomyocytes when treated with 1% dimethyl sulfoxide (DMSO), however, CL6-Xwnt-8 cells did not differentiate into beating cardiomyocytes under the same condition. RT-PCR showed that expression of Csx/Nkx2-5, a cardiac-specific transcription factor, was significantly reduced in CL6-Xwnt-8 cells compared with parental P19CL6 cells, suggesting that Xwnt-8 suppressed Csx/Nkx2-5 transcription regulating P19CL6 differentiation. CL6-hDkk-1 cells differentiated into beating cardiomyocytes and expressed Csx/Nkx2-5 as much as parental P 19CL6 cells, however, did not differentiate without 1% DMSO, indicating the possibility that additional stimuli are necessary for the differentiation into cardiomyocytes. Together, these results suggest that Wnt signal regulates cardiomyocyte differentiation by reducing the expression of Csx/Nkx2-5.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (9 results)

All Other

All Publications (9 results)

  • [Publications] Toko H et al.: "Angiotensin II type 1a receptor mediates doxorubicin-induced cardiomyopathy"Hypertens Res. 25. 597-603 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Monzen K et al.: "Dual effects of the homeobox transcription factor csx/Nkx2-5 cardiomyocytes."Biochem Biophys Res Commun. 298. 493-500 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Monzen K, Zhu W, Kasai H, Hiroi Y, Hosoda T, Akazawa H, Zou Y, Hayashi D, Yamazaki T, Nagai R, Komuro I: "Dual effects of the homeobox transcription factor Csx/Nkx2-5 on cardiomyocytes."Biochem Biophys Res Commun. 298. 493-500 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Toko H, Oka T, Zou Y, Sakamoto M, Mizukami M, Sano M, Yamamoto R, Sugaya T, Komuro I: "Angiotensin II type 1a receptor mediates doxorubicin-induced cardiomyopathy."Hypertens Res. 25. 597-603 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Toko H et al.: "Angiotensin II type 1a receptor mediates doxorubicin-induced cardiomyopathy"Hypertens Res. 25. 597-603 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Monzen K et al.: "Dual effects of the homeobox transcription factor csx/Nkx2-5 cardiomyocytes"Biochem Biophys Res Commun. 298. 493-500 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Toko H et al.: "Csx/Nkx2-5 is requied for homeostasis and survival of cardiac myocytes in the adult heart"J Biol Chem. 277. 24735-24743 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Toko H et al.: "Angiotensin II type 1a receptor mediates doxorubicin-induced cardiomyopathy"Hypertens Res. 25. 597-603 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Toko H et al.: "Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart"J Biol Chem. 277. 24735-24743 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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