Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo

Nature volume 415, pages168–171(2002)Cite this article

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Abstract

Extracellular elastic fibres provide mechanical elasticity to tissues and contribute towards the processes of organ remodelling by affecting cell–cell signalling1,2. The formation of elastic fibres requires the assembly and crosslinking of tropoelastin monomers, and organization of the resulting insoluble elastin matrix into functional fibres. The molecules and mechanisms involved in this process are unknown. Fibulin-5 (also known as EVEC/DANCE) is an extracellular matrix protein abundantly expressed in great vessels and cardiac valves during embryogenesis, and in many adult tissues including the aorta, lung, uterus and skin, all of which contain abundant elastic fibres3,4. Here we show that fibulin-5 is a calcium-dependent, elastin-binding protein that localizes to the surface of elastic fibres in vivo. fibulin-5-/- mice develop marked elastinopathy owing to the disorganization of elastic fibres, with resulting loose skin, vascular abnormalities and emphysematous lung. This phenotype, which resembles the cutis laxa syndrome in humans5, reveals a critical function for fibulin-5 as a scaffold protein that organizes and links elastic fibres to cells. This function may be mediated by the RGD motif in fibulin-5, which binds to cell surface integrins, and the Ca2+-binding epidermal growth factor (EGF) repeats, which bind elastin.

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Figure 1: Gross phenotype of fibulin-5-/- mice.
Figure 2: Histological analysis of fibulin-5-/- mice.
Figure 3: Characterization of aorta in fibulin-5-/- mice.
Figure 4: Interaction of fibulin-5 and elastin.

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Acknowledgements

We thank R. Kowal and B. Abrams for reagents. We thank J. Shelton, J. Stark, S. Yokoyama and A. Rankin for technical assistance, A. Tizenor for graphic assistance, and M. Brown for critical reading of the manuscript. This work was supported in part by the American Heart Association (H.Y.), National Institutes of Health (E.C.D. and E.N.O.) and the D.W. Reynolds Foundation for Clinical Cardiovascular Research (E.N.O.). M.Y. is an investigator for the Howard Hughes Medical Institutes.

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Affiliations

  1. Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, 75390, Texas, USA

    • Hiromi Yanagisawa
    • , James A. Richardson
    •  & Eric N. Olson

  2. Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, 75390, Texas, USA

    • Elaine C. Davis

  3. Department of Pathology, University of Texas Southwestern Medical Center at Dallas, 75390, Texas, USA

    • James A. Richardson

  4. Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, 75390, Texas, USA

    • Takashi Ouchi
    •  & Masashi Yanagisawa

  5. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 75390, Texas, USA

    • Takashi Ouchi
    •  & Masashi Yanagisawa

  6. Department of Biochemistry, University of Texas Health Center at Tyler, 75708, Texas, USA

    • Barry C. Starcher

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Correspondence to Eric N. Olson.

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Yanagisawa, H., Davis, E., Starcher, B. et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415, 168–171 (2002) doi:10.1038/415168a

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