Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice
Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice
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DOI：
10.1093/hmg/ddm264
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发表时间：
2007-12-15
影响因子：
3.5
通讯作者：
Marmorstein, Lihua Y.
中科院分区：
文献类型：
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作者：
McLaughlin, Precious J.;Bakall, Benjamin;Marmorstein, Lihua Y.
EFEMP1 基因突变会导致 Malattia Leventinese，这是一种遗传性黄斑变性疾病，与年龄相关性黄斑变性非常相似。 EFEMP1 编码 fibulin-3，一种功能未知的细胞外基质蛋白。为了研究其生物学作用，通过有针对性的破坏使小鼠 Efemp1 基因失活。 Efemp1(-/-)小鼠表现出繁殖能力下降，并表现出早期出现的与衰老相关的表型，包括寿命缩短、体重减轻、脊柱前凸、毛发生长减少以及全身脂肪、肌肉和器官萎缩。然而，这些小鼠似乎具有正常的伤口愈合能力。 C57BL/6 遗传背景的 Efemp1(-/-) 小鼠出现多种大疝气，包括腹股沟疝气、骨盆脱垂和剑突突出。相比之下，BALB/c 背景下的 Efemp1(-/-) 小鼠很少有任何形式的疝气，这表明不同小鼠品系中存在 fibulin-3 功能修饰剂。组织学分析显示筋膜中的弹性纤维显着减少，筋膜是维持和保护全身结构的薄层结缔组织。在Efemp1(-/-)小鼠中没有发现明显的黄斑变性相关缺陷，这表明fibulin-3功能的丧失并不是EFEMP1突变引起黄斑变性的机制。这些数据表明 fibulin-3 在维持筋膜结缔组织的完整性和调节衰老方面发挥着重要作用。
A mutation in the EFEMP1 gene causes Malattia Leventinese, an inherited macular degenerative disease with strong similarities to age-related macular degeneration. EFEMP1 encodes fibulin-3, an extracellular matrix protein of unknown function. To investigate its biological role, the murine Efemp1 gene was inactivated through targeted disruption. Efemp1(-/-) mice exhibited reduced reproductivity, and displayed an early onset of aging-associated phenotypes including reduced lifespan, decreased body mass, lordokyphosis, reduced hair growth, and generalized fat, muscle and organ atrophy. However, these mice appeared to have normal wound healing ability. Efemp1(-/-) mice on a C57BL/6 genetic background developed multiple large hernias including inguinal hernias, pelvic prolapse and protrusions of the xiphoid process. In contrast, Efemp1(-/-) mice on a BALB/c background rarely had any forms of hernias, indicating the presence of modifiers for fibulin-3's function in different mouse strains. Histological analysis revealed a marked reduction of elastic fibers in fascia, a thin layer of connective tissue maintaining and protecting structures throughout the body. No apparent macular degeneration associated defects were found in Efemp1(-/-) mice, suggesting that loss of fibulin-3 function is not the mechanism by which the mutation in EFEMP1 causes macular degeneration. These data demonstrate that fibulin-3 plays an important role in maintaining the integrity of fascia connective tissues and regulates aging.