Fibulin-5/DANCE is essential for elastogenesis in vivo

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.
Figure 2: Gross phenotypes and physiological studies of fibulin-5-/- mice.
Figure 3: Emphysema and secondary cardiac phenotype in fibulin-5-/- mice.
Figure 4: Fine structure of elastic fibres in tissues of fibulin-5+/+ and fibulin-5-/- mice.
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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Correspondence to Kenneth R. Chien.

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The authors declare no competing financial interests.

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