Abstract
The eye lens is composed of fibre cells, which develop from the epithelial cells on the anterior surface of the lens1,2,3. Differentiation into a lens fibre cell is accompanied by changes in cell shape, the expression of crystallins4 and the degradation of cellular organelles5,6. The loss of organelles is believed to ensure the transparency of the lens, but the molecular mechanism behind this process is not known. Here we show that DLAD (‘DNase II-like acid DNase’7, also called DNase IIβ8) is expressed in human and murine lens cells, and that mice deficient in the DLAD gene are incapable of degrading DNA during lens cell differentiation—the undigested DNA accumulates in the fibre cells. The DLAD-/- mice develop cataracts of the nucleus lentis, and their response to light on electroretinograms is severely reduced. These results indicate that DLAD is responsible for the degradation of nuclear DNA during lens cell differentiation, and that if DNA is left undigested in the lens, it causes cataracts of the nucleus lentis, blocking the light path.
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References
McAvoy, J. W., Chamberlain, C. G., de Iongh, R. U., Hales, A. M. & Lovicu, F. J. Lens development. Eye 13, 425–437 (1999)
Grainger, R. M., Henry, J. J., Saha, M. S. & Servetnick, M. Recent progress on the mechanisms of embryonic lens formation. Eye 6, 117–122 (1992)
Piatigorsky, J. Lens differentiation in vertebrates. A review of cellular and molecular features. Differentiation 19, 134–153 (1981)
Wistow, G. J. & Piatigorsky, J. Lens crystallins: The evolution and expression of proteins for a highly specialized tissue. Annu. Rev. Biochem. 57, 479–504 (1988)
Bassnett, S. Lens organelle degradation. Exp. Eye Res. 74, 1–6 (2002)
Bassnett, S. & Mataic, D. Chromatin degradation in differentiating fiber cells of the eye lens. J. Cell Biol. 137, 37–49 (1997)
Shiokawa, D. & Tanuma, S. DLAD, a novel mammalian divalent cation-independent endonuclease with homology to DNase II. Nucleic Acids Res. 27, 4083–4089 (1999)
Krieser, R. J., MacLea, K. S., Park, J. P. & Eastman, A. The cloning, genomic structure, localization, and expression of human deoxyribonuclease IIβ. Gene 269, 205–216 (2001)
Kawane, K. et al. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science 292, 1546–1549 (2001)
Krieser, R. J. et al. Deoxyribonuclease IIa is required during the phagocytic phase of apoptosis and its loss causes lethality. Cell Death Differ. 9, 956–962 (2002)
Kawane, K. et al. Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation. Nature Immunol. 4, 138–144 (2003)
Nagata, S., Nagase, H., Kawane, K., Mukae, N. & Fukuyama, H. Degradation of chromosomal DNA during apoptosis. Cell Death Differ. 10, 108–116 (2003)
Kuwabara, T. & Imaizumi, M. Denucleation process of the lens. Invest. Ophthalmol. Vis. Sci. 13, 973–981 (1974)
Torriglia, A. et al. L-DNase II, a molecule that links proteases and endonucleases in apoptosis, derives from the ubiquitous serpin leukocyte elastase inhibitor. Mol. Cell. Biol. 18, 3612–3619 (1998)
Bernardi, G., (ed. Boyer, P. D.)) The Enzymes, 271–287 (Academic, New York, 1971)
Wride, M. A. & Sanders, E. J. Nuclear degeneration in the developing lens and its regulation by TNFα. Exp. Eye Res. 66, 371–383 (1998)
Dahm, R., Gribbon, C., Quinlan, R. A. & Prescott, A. R. Changes in the nucleolar and coiled body compartments precede lamina and chromatin reorganization during fibre cell denucleation in the bovine lens. Eur. J. Cell Biol. 75, 237–246 (1998)
Ishizaki, Y., Jacobson, M. D. & Raff, M. C. A role for caspases in lens fiber differentiation. J. Cell Biol. 140, 153–158 (1998)
Chaudun, E. et al. DNA strand breakage during physiological apoptosis of the embryonic chick lens: Free 3′ OH end single strand breaks do not accumulate even in the presence of a cation-independent deoxyribonuclease. J. Cell. Physiol. 158, 354–364 (1994)
McIlroy, D. et al. An auxiliary mode of apoptotic DNA fragmentation provided by phagocytes. Genes Dev. 14, 549–558 (2000)
Klionsky, D. J. & Emr, S. D. Autophagy as a regulated pathway of cellular degradation. Science 290, 1717–1721 (2000)
Klionsky, D. J. & Ohsumi, Y. Vacuolar import of proteins and organelles from the cytoplasm. Annu. Rev. Cell Dev. Biol. 15, 1–32 (1999)
Vrensen, G. F., Graw, J. & De Wolf, A. Nuclear breakdown during terminal differentiation of primary lens fibres in mice: A transmission electron microscopic study. Exp. Eye Res. 52, 647–659 (1991)
Laird, P. W. et al. Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 19, 4293 (1991)
Sambrook, J. & Russell, D. W. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 2001)
Fleming, T. P., Song, Z. & Andley, U. P. Expression of growth control and differentiation genes in human lens epithelial cells with extended life span. Invest. Ophthalmol. Vis. Sci. 39, 1387–1398 (1998)
Imoto, Y. et al. Effects of RGD peptides on cells derived from the human eye. Jpn J. Ophthal. (in the press)
Ezaki, J., Wolfe, L. S. & Kominami, E. Specific delay in the degradation of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid lipofuscinosis is derived from cellular proteolytic dysfunction rather than structural alteration of subunit c. J. Neurochem. 67, 1677–1687 (1996)
Masu, M. et al. Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene. Cell 80, 757–765 (1995)
Acknowledgements
We thank E. Kominami for providing us with rabbit antibody against the subunit β of mitochondrial ATP synthase. We thank K. Miwa for cloning of mouse DLAD gene, Y. Seto for maintaining the mice, and M. Fujii 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.
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Nishimoto, S., Kawane, K., Watanabe-Fukunaga, R. et al. Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens. Nature 424, 1071–1074 (2003). https://doi.org/10.1038/nature01895
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DOI: https://doi.org/10.1038/nature01895
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