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Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation

Nature Immunology volume 4, pages 138–144 (2003)Cite this article

Abstract

Apoptosis is often accompanied by the degradation of chromosomal DNA. Caspase-activated DNase (CAD) is an endonuclease that is activated in dying cells, whereas DNase II is present in the lysosomes of macrophages. Here, we show that CAD−/− thymocytes did not undergo apoptotic DNA degradation. But, when apoptotic cells were phagocytosed by macrophages, their DNA was degraded by DNase II. The thymus of DNase II−/−CAD−/− embryos contained many foci carrying undigested DNA and the cellularity was severely reduced due to a block in T cell development. The interferon-β gene was strongly up-regulated in the thymus of DNase II−/−CAD−/− embryos, suggesting that when the DNA of apoptotic cells is left undigested, it can activate innate immunity leading to defects in thymic development.

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Figure 1: Targeted disruption of the CAD gene by homologous recombination.
Figure 2: DNA degradation of apoptotic cells in macrophages.
Figure 3: Impaired thymic development in DNase-targeted mouse embryos.
Figure 4: Accumulation of DNA in thymic macrophages of DNase-targeted embryos.

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Acknowledgements

We thank M. Adachi for help in the initial stage of this study; K. Miwa for PCR; A. Kudo for CMG-12 cells; K. Ishihara for the advice on the fetal thymus organ culture; and S. Aoyama and M. Harayama for secretarial assistance. This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports, and Culture in Japan. K.K. is supported by a research fellowship from the Japan Society for the Promotion of Science.

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Author notes

  1. Hidehiro Fukuyama

    Present address: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY, 10021, USA

Authors and Affiliations

  1. Department of Genetics, Osaka University Medical School, Osaka, 565-0871, Japan

    Kohki Kawane, Hidehiro Fukuyama, Hideyuki Yoshida, Hiroko Nagase & Shigekazu Nagata

  2. Departments of Cell Biology and Neuroscience, Osaka University Medical School, Osaka, 565-0871, Japan

    Yoshiyuki Ohsawa & Yasuo Uchiyama

  3. Department of Bacterial Infections, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan

    Kazuhisa Okada & Tetsuya Iida

  4. Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka, 565-0871, Japan

    Shigekazu Nagata

  5. Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Osaka, 565-0871, Japan

    Shigekazu Nagata

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Kawane, K., Fukuyama, H., Yoshida, H. et al. Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation. Nat Immunol 4, 138–144 (2003). https://doi.org/10.1038/ni881

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