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2004 Fiscal Year Final Research Report Summary

MOLECULAR MECHANISM OF CELL DEATH AND ITS PHYSIOLOGICAL ROLE

Research Project

Project/Area Number 12219213
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionOsaka University

Principal Investigator

NAGATA Shigekazu  Osaka University, Graduate School of Frontier Biosciences, Professor, 生命機能研究科, 教授 (70114428)

Co-Investigator(Kenkyū-buntansha) FUKUNAGA Rikiro  Osaka University, Graduate School of Frontier Biosciences, Associate Professor, 生命機能研究科, 助教授 (40189965)
TANAKA Masato  Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (00294059)
FUKUYAMA Hidehiro  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70303956)
KAWANE Koki  Osaka University, Graduate School of Frontier Biosciences, Assistant Professor, 生命機能研究科, 助手 (60362589)
Project Period (FY) 2000 – 2004
Keywordsapoptosis / macrophages / DNA degradation / enucleation of erythroid cells / autoimmune disease / DNase II / Caspase-activated DNase / innate immunity
Research Abstract

In this project, we have examined the molecular mechanism of apoptotic DNA degradation, and its physiological role. That is, we characterized the enzymatic properties of CAD (caspase-activated DNase) that was previously identified in our laboratory as a DNase activated during apoptosis. We then demonstrated by establishing the CAD-deficient mice that CAD is solely responsible for the cell-autonomous DNA degradation in apoptotic cells. Analysis of the apoptotic cells in the CAD-deficient mice showed that the DNA of apoptotic cells could be degraded in vivo by DNase II present in the macrophages after the dead cells were engulfed by phagocytes. The DNase II-deficient mice were then established, and the analysis of the mice showed that the DNase digests not only DNA of apoptotic cells, but also the DNA expelled from erythroid precursor cells. The DNase II-null mice were embryonic lethal, which was due to the interferon-β that was produced in macrophages carrying a large amount of undigested DNA by the activation of innate immunity. Using the knowledge that the DNA of apoptotic cells can be cleaved by macrophages after the dead cells are engulfed, we established a reliable assay method for engulfment of apoptotic cells. Using this system, we identified a factor called Milk Fat Globule-EGF8 (MFG-E8). MFG-E8 recognized apoptotic cells by binding to phosphatidylserine exposed to the apoptotic cells. MFG-E8 also bound to macrophages via integrin, indicating that it serves as a bridge between apoptotic cells and phagocytes. MFG-E8 was found to be expressed in a set of macrophages including tingible-body macrophages in the germinal centers of the spleen, and in immature dendritic cells. The MFG-E8-deficient mice accumulated unengulfed apoptotic cells in the germinal centers of the spleen, and developed autoimmune diseases such as nephritis, indicating that if apoptotic cells are not swiftly cleared from our bodies, they will induce the autoimmunity.

  • Research Products

    (8 results)

All 2004 2003 2002 2001

All Journal Article (8 results)

  • [Journal Article] Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice.2004

    • Author(s)
      Hanayama, R. et al.
    • Journal Title

      Science 304

      Pages: 1147-1150

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation.2003

    • Author(s)
      Kawane, K. et al.
    • Journal Title

      Nat Immunol 4

      Pages: 138-144

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens.2003

    • Author(s)
      Nishimoto, S. et al.
    • Journal Title

      Nature 424

      Pages: 1071-1074

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation2003

    • Author(s)
      Kawane, K. et al.
    • Journal Title

      Nat Immunol 4

      Pages: 138-144

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Identification of a factor that links apoptotic cells to phagocytes2002

    • Author(s)
      Hanayama, R. et al.
    • Journal Title

      Nature 417

      Pages: 182-187

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Identification of a factor that links apoptotic cells to phagocytes.2002

    • Author(s)
      Hanayama, R. et al.
    • Journal Title

      Nature 417

      Pages: 182-187

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Requirement of DNase II for definitive erythropoiesis in themo use fetal liver.2001

    • Author(s)
      Kawane, K. et al.
    • Journal Title

      Science 292

      Pages: 1546-1549

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver.2001

    • Author(s)
      Kawane, K. et al.
    • Journal Title

      Science 292

      Pages: 1546-1549

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2008-05-27  

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