Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice.
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.
McLaughlin
Precious J
PJ
Department of Ophthalmology and Vision Science, University of Arizona, Tucson, AZ 85711, USA.
Chen
Qiuyun
Q
Horiguchi
Masahito
M
Starcher
Barry C
BC
Stanton
J Brett
JB
Broekelmann
Thomas J
TJ
Marmorstein
Alan D
AD
McKay
Brian
B
Mecham
Robert
R
Nakamura
Tomoyuki
T
Marmorstein
Lihua Y
LY
D000818:Animals; D001011:Aorta / Q000002:abnormalities / Q000196:embryology; D002478:Cells, Cultured; D003895:Desmosine / Q000378:metabolism; D004547:Elastic Tissue / Q000002:abnormalities / Q000502:physiology*; D004549:Elastin / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism*; D005313:Fetal Death / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D008168:Lung / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D014333:Tropoelastin / Q000378:metabolism
C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D014333:Tropoelastin; D003895:Desmosine; D004549:Elastin; D008249:Protein-Lysine 6-Oxidase