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Molecular and Cellular Biology, February 2007, p. 1083-1095, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01330-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Molecular Analysis of Fibulin-5 Function during De Novo Synthesis of Elastic Fibers{triangledown}

Qian Zheng,1 Elaine C. Davis,2 James A. Richardson,1,3 Barry C. Starcher,4 Tiansen Li,5 Robert D. Gerard,1,6 and Hiromi Yanagisawa1*

Departments of Molecular Biology,1 Pathology,3 Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, Texas,6 Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada,2 Department of Biochemistry, University of Texas Health Center, Tyler, Texas,4 Department of Opthalmology, Harvard Medical School and Massachusetts Eye & Ear Infirmary, Boston, Massachusetts5

Received 20 July 2006/ Returned for modification 1 September 2006/ Accepted 13 November 2006

Elastic fibers contribute to the structural support of tissues and to the regulation of cellular behavior. Mice deficient for the fibulin-5 gene (fbln5–/–) were used to further elucidate the molecular mechanism of elastic fiber assembly. Major elastic fiber components were present in the skin of fbln5–/– mice despite a dramatic reduction of mature elastic fibers. We found that fibulin-5 preferentially bound the monomeric form of elastin through N-terminal and C-terminal elastin-binding regions and to a preexisting matrix scaffold through calcium-binding epidermal growth factor (EGF)-like (CB-EGF) domains. We further showed that adenovirus-mediated gene transfer of fbln5 was sufficient to regenerate elastic fibers and increase elastic fiber-cell connections in vivo. A mutant fibulin-5 lacking the first 28 amino acids of the first CB-EGF domain, however, was unable to rescue elastic fiber defects. Fibulin-5 thus serves as an adaptor molecule between monomeric elastin and the matrix scaffold to aid in elastic fiber assembly. These results also support the potential use of fibulin-5 as a therapeutic agent for the treatment of elastinopathies.

* Corresponding author. Mailing address: Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9148. Phone: (214) 648-7723. Fax: (214) 648-1488. E-mail: hiromi.yanagisawa{at}utsouthwestern.edu.

{triangledown} Published ahead of print on 27 November 2006.

Molecular and Cellular Biology, February 2007, p. 1083-1095, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01330-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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