Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice
Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice
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DOI：
10.1128/mcb.26.5.1700-1709.2006
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发表时间：
2006-03-01
影响因子：
5.3
通讯作者：
Marmorstein, LY
中科院分区：
文献类型：
--
作者：
McLaughlin, PJ;Chen, QY;Marmorstein, LY
弹性纤维为组织提供弹性，这对动脉、肺、皮肤和其他动态器官的功能至关重要。弹性的丧失是衰老和疾病的主要因素。然而，弹性纤维的发育和组装的机制知之甚少。在这里，我们表明，缺乏fibulin-4，细胞外基质分子，废除弹性。通过基因靶向产生的fibulin-4（-/-）小鼠表现出严重的肺和血管缺陷，包括肺气肿、动脉弯曲、不规则、动脉瘤、破裂和导致的血管瘤。所有的纯合子小鼠围产期死亡。最早发现的异常是胚胎第12.5天（E12.5）降主动脉infibulin-4（-/-）胚胎均匀变窄。在E15.5时，主动脉迂曲和不规则变得明显。组织学分析表明，fibulin-4（-/-）小鼠不发育完整的弹性纤维，但含有不规则的弹性蛋白聚集体。电子显微镜显示，弹性蛋白聚集体是非常不寻常的，因为它们包含均匀分布的棒状细丝，与正常弹性纤维的无定形外观相反。锁链素分析表明，在fibulin-4（-/-）组织中的弹性蛋白交联大大减少。然而，原弹性蛋白或赖氨酰氧化酶mRNA的表达不受fibulin-4（-/-）小鼠的影响。此外，fibulin-4强烈相互作用与原弹性蛋白和共定位与弹性纤维在文化。这些结果表明，fibulin-4在弹性蛋白生成中起着不可替代的作用。
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.