1. UCSD-Salk Program in Molecular Medicine and the UCSD Institute of Molecular Medicine, University of California, San Diego, La Jolla, California, 92093, USA
2. Vascular Biology, the Scripps Research Institute, La Jolla, California 92037, USA
3. Division of Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
4. Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
5. Center for Molecular Biology and Genetics, Kyoto University, Kyoto 606-8501, Japan

Correspondence to: Kenneth R. Chien¹ Correspondence and requests for materials should be addressed to K.R.C. (e-mail: Email: kchien@ucsd.edu).

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 skin^{1, 2}. Although elastic fibres are known to be composed of microfibril proteins (for example, fibrillins and latent transforming growth factor (TGF)--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 v3, v5 and 91 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.