1. Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA
2. Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA
3. Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA
4. Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA
5. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA
6. Department of Biochemistry, University of Texas Health Center at Tyler, Texas 75708, USA

Correspondence to: Eric N. Olson¹ Correspondence and requests for materials should be addressed to E.N.O. (e-mail: Email: eolson@hamon.swmed.edu) or H.Y. (e-mail: Email: hkyanagisawa@aol.com).

Abstract

Extracellular elastic fibres provide mechanical elasticity to tissues and contribute towards the processes of organ remodelling by affecting cell–cell signalling^{1, 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 fibres^{3, 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.