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

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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.


  1. 1

    Mecham, R. P. & Davis, E. C. in Extracellular Matrix Assembly and Structure (eds Yurchenco, P. D., Birk, D. E. & Mecham, R. P.) 281–314 (Academic, New York, 1994).

  2. 2

    Li, D. Y. et al. Elastin is an essential determinant of arterial morphogenesis. Nature 393, 276–280 (1998).

  3. 3

    Kowal, R. C., Richardson, J. A., Miano, J. M. & Olson, E. N. EVEC, a novel epidermal growth factor-like repeat-containing protein upregulated in embryonic and diseased adult vasculature. Circ. Res. 84, 1166–1176 (1999).

  4. 4

    Nakamura, T. et al. DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon-injured arteries. J. Biol. Chem. 274, 22476–22483 (1999).

  5. 5

    Milewicz, D. M., Urban, Z. & Boyd, C. Genetic disorders of the elastic fiber system. Matrix Biol. 19, 471–480 (2000).

  6. 6

    Sasaki, T. et al. Tropoelastin binding to fibulins, nidogen-2 and other extracellular matrix proteins. FEBS Lett. 460, 280–284 (1999).

  7. 7

    Doliana, R. et al. EMILIN, a component of the elastic fiber and a new member of the C1q/tumor necrosis factor superfamily of proteins. J. Biol. Chem. 274, 16773–16781 (1999).

  8. 8

    Trask, B. C. et al. Posttranslational modifications of microfibril assocoated glycoprotein-1. Biochemistry 40, 4372–4380 (2001).

  9. 9

    Trask, T. M. et al. Interaction of tropoelastin with the amino-terminal domains of fibrillin-1 and fibrillin-2 suggests a role for the fibrillins in elastic fiber assembly. J. Biol. Chem. 275, 24400–24406 (2000).

  10. 10

    Pereira, L. et al. Targeting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nature Genet. 17, 218–222 (1997).

  11. 11

    Pereira, L. et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc. Natl Acad. Sci. USA 96, 3819–3823 (1997).

  12. 12

    Chaudhry, S. S. et al. Mutation of the gene encoding fibrillin-2 results in syndactyly in mice. Hum. Mol. Genet. 10, 835–843 (2001).

  13. 13

    Arteaga-Solis, E. et al. Regulation of limb patterning by extracellular microfibrils. J. Cell Biol. 154, 275–281 (2001).

  14. 14

    Starcher, B. & Conrad, M. A role for neutrophil elastase in the progression of solar elastosis. Connect. Tissue Res. 31, 133–140 (1995).

  15. 15

    Davis, E. C. Smooth muscle cell to elastic lamina connections in the developing mouse aorta: role in aortic medial organization. Lab. Invest. 68, 89–99 (1993).

  16. 16

    Davis, E. C. Immunolocalization of microfibril and microfibril-associated proteins in the subendothelial matrix of the developing mouse aorta. J. Cell Sci. 107, 727–736 (1994).

  17. 17

    Reinhardt, D. P. et al. Fibrillin-1: organization in microfibrils and structural properties. J. Mol. Biol. 258, 104–116 (1996).

  18. 18

    Reinhardt, D. P. et al. Fibrillin-1 and fibulin-2 interact and are colocalized in some tissues. J. Biol. Chem. 271, 19489–19496 (1996).

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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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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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