期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 26, 期 5, 页码 1700-1709出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.26.5.1700-1709.2006
关键词
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资金
- NEI NIH HHS [R01 EY013160, EY13160, EY13847, R01 EY013847, R56 EY013160] Funding Source: Medline
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 infibulin-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 infibulin-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.
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