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Molecular and Cellular Biology, March 2006, p. 1700-1709, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1700-1709.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Targeted Disruption of Fibulin-4 Abolishes Elastogenesis and Causes Perinatal Lethality in Mice

Precious J. McLaughlin,^1, Qiuyun Chen,^1, Masahito Horiguchi,² Barry C. Starcher,³ J. Brett Stanton,¹ Thomas J. Broekelmann,⁴ Alan D. Marmorstein,^1,5 Brian McKay,^1,6 Robert Mecham,⁴ Tomoyuki Nakamura,² and Lihua Y. Marmorstein^1,6,7*

Department of Ophthalmology and Vision Science,¹ Optical Sciences Center,⁵ Department of Cell Biology and Anatomy,⁶ Department of Physiology, University of Arizona, Tucson, Arizona,⁷ Horizontal Medical Research Organization, Kyoto University School of Medicine, Kyoto, Japan,² Department of Biochemistry, University of Texas Health Center at Tyler, Texas,³ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri⁴

Received 20 October 2005/ Returned for modification 27 November 2005/ Accepted 5 December 2005

Elastic fibers provide tissues with elasticity which is critical to the function of arteries, lungs, skin, and other dynamic organs. Loss of elasticity is a major contributing factor in aging and diseases. However, the mechanism of elastic fiber development and assembly is poorly understood. Here, we show that lack of fibulin-4, an extracellular matrix molecule, abolishes elastogenesis. fibulin-4^–/– mice generated by gene targeting exhibited severe lung and vascular defects including emphysema, artery tortuosity, irregularity, aneurysm, rupture, and resulting hemorrhages. All the homozygous mice died perinatally. The earliest abnormality noted was a uniformly narrowing of the descending aorta in fibulin-4^–/– embryos at embryonic day 12.5 (E12.5). Aorta tortuosity and irregularity became noticeable at E15.5. Histological analysis demonstrated that fibulin-4^–/– mice do not develop intact elastic fibers but contain irregular elastin aggregates. Electron microscopy revealed that the elastin aggregates are highly unusual in that they contain evenly distributed rod-like filaments, in contrast to the amorphous appearance of normal elastic fibers. Desmosine analysis indicated that elastin cross-links in fibulin-4^–/– tissues were largely diminished. However, expression of tropoelastin or lysyl oxidase mRNA was unaffected in fibulin-4^–/– mice. In addition, fibulin-4 strongly interacts with tropoelastin and colocalizes with elastic fibers in culture. These results demonstrate that fibulin-4 plays an irreplaceable role in elastogenesis.

P.J.M. and Q.C. contributed equally to this work.

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