Fibulin-5/DANCE is essential for elastogenesis in vivo (original) (raw)

Nature volume 415, pages 171–175 (2002) Cite this article

Abstract

The elastic fibre system has a principal role in the structure and function of various types of organs that require elasticity, such as large arteries, lung and skin1,2. Although elastic fibres are known to be composed of microfibril proteins (for example, fibrillins and latent transforming growth factor (TGF)-β-binding proteins) and polymerized elastin, the mechanism of their assembly and development is not well understood. Here we report that fibulin-5 (also known as DANCE), a recently discovered integrin ligand3, is an essential determinant of elastic fibre organization. _fibulin-5_-/- mice generated by gene targeting exhibit a severely disorganized elastic fibre system throughout the body. _fibulin-5_-/- mice survive to adulthood, but have a tortuous aorta with loss of compliance, severe emphysema, and loose skin (cutis laxa). These tissues contain fragmented elastin without an increase of elastase activity, indicating defective development of elastic fibres. Fibulin-5 interacts directly with elastic fibres in vitro, and serves as a ligand for cell surface integrins αvβ3, αvβ5 and α9β1 through its amino-terminal domain. Thus, fibulin-5 may provide anchorage of elastic fibres to cells, thereby acting to stabilize and organize elastic fibres in the skin, lung and vasculature.

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Figure 1: In situ hybridization of P0.5 fibulin-5+/+ (a) and _fibulin-5_-/- (b) transverse sections at the level of the cardiac outflow tract, probed with 35S-labelled fibulin-5 riboprobes.

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Figure 2: Gross phenotypes and physiological studies of _fibulin-5_-/- mice.

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Figure 3: Emphysema and secondary cardiac phenotype in _fibulin-5_-/- mice.

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Figure 4: Fine structure of elastic fibres in tissues of fibulin-5+/+ and _fibulin-5_-/- mice.

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Figure 5: Fibulin-5 binding to elastic fibres and to cell surface integrins.

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Acknowledgements

We thank Y. Gu, J. Anderson, T. Mikuni, N. Tomikawa and C. Suzuki for technical assistance; P. L. Haywood-Reid for electron microscopy; M. Hoshijima and H. Yasukawa for advice on experimental design; and S. Evans and J. Chen for suggestions in preparing the manuscript. This study was supported by the National Institutes of Health, the Jean LeDucq Foundation, and the American Heart Association Endowed Chair to K.R.C. T.N. was supported by the American Heart Association Western Affiliate Postdoctoral Fellowship.

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Authors and Affiliations

  1. UCSD-Salk Program in Molecular Medicine and the UCSD Institute of Molecular Medicine, University of California, San Diego, La Jolla, 92093, California, USA
    Tomoyuki Nakamura, Pilar Ruiz Lozano, Yasuhiro Ikeda, Yoshitaka Iwanaga, Susumu Minamisawa, Ching-Feng Cheng, Nancy Dalton, John Ross Jr & Kenneth R. Chien
  2. Vascular Biology, the Scripps Research Institute, La Jolla, 92037, California, USA
    Yoshitaka Iwanaga & Yoshikazu Takada
  3. Division of Cardiovascular Research, The Hospital for Sick Children, Toronto, M5G 1X8, Ontario, Canada
    Aleksander Hinek
  4. Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
    Kazuhiro Kobuke & Tasuku Honjo
  5. Center for Molecular Biology and Genetics, Kyoto University, Kyoto, 606-8501, Japan
    Kei Tashiro

Authors

  1. Tomoyuki Nakamura
  2. Pilar Ruiz Lozano
  3. Yasuhiro Ikeda
  4. Yoshitaka Iwanaga
  5. Aleksander Hinek
  6. Susumu Minamisawa
  7. Ching-Feng Cheng
  8. Kazuhiro Kobuke
  9. Nancy Dalton
  10. Yoshikazu Takada
  11. Kei Tashiro
  12. John Ross Jr
  13. Tasuku Honjo
  14. Kenneth R. Chien

Corresponding author

Correspondence toKenneth R. Chien.

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The authors declare no competing financial interests.

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Nakamura, T., Lozano, P., Ikeda, Y. et al. Fibulin-5/DANCE is essential for elastogenesis in vivo.Nature 415, 171–175 (2002). https://doi.org/10.1038/415171a

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