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Production of muscular dystrophy mice by molecular engineering

分子工程生产肌营养不良症小鼠

基本信息

批准号：
09470156
负责人：
SHIMIZU Teruo
金额：
$ 8.38万
依托单位：
Teikyo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Caveolin-3 is the muscle-specific isoform of the caveolin protein family, which is a major component of caveolae, small membrane invaginations found in most cell types. Caveolins play important roles in the formation of caveola membranes, acting as scaffolding proteins to organize and concentrate lipid-modified signaling molecules, and modulate a signaling pathway. For instance, caveolin-3 interacts with neuronal nitric-oxide synthase (nNOS) and inhibits its catalytic activity. Via the syntrophin-nNOS linkage, caveolin-3 also interacts with the dystroglycan complex, which is a major player of muscle cell adhesion to laminin. Recently, specific mutations in the caveolin-3 gene, including the Pro104Leu missense mutation, have been shown to cause an autosomal dominant limb-girdle muscular dystrophy (LGMD1C), which is characterized by the deficiency of caveolin-3 in the sarcolemma. However, the molecular mechanism by which these mutations cause the deficiency of caveolin-3 and muscle cell degeneration remains elusive. Here we generated transgenic mice expressing the Pro104Leu mutant caveolin-3. They showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, indicating a dominant negative effect of mutant caveolin-3. Interestingly, we found a great increase of nNOS activity in their skeletal muscle, which, we propose, may play a role in muscle fiber degeneration in caveolin-3.

Caveolin-3是Caveolin蛋白家族的肌肉特异性同种型，其是在大多数细胞类型中发现的小膜内陷的Caveolae的主要组分。窖蛋白在窖膜的形成中起重要作用，作为支架蛋白组织和浓缩脂质修饰的信号分子，并调节信号通路。例如，小窝蛋白-3与神经元一氧化氮合酶（nNOS）相互作用并抑制其催化活性。通过syntrophin-nNOS连接，小窝蛋白-3还与肌营养不良蛋白聚糖复合物相互作用，肌营养不良蛋白聚糖复合物是肌细胞粘附于层粘连蛋白的主要参与者。最近，在小窝蛋白-3基因的特定突变，包括Pro 104 Leu错义突变，已被证明会导致常染色体显性肢带型肌营养不良症（LGMD 1C），其特征是肌膜中的小窝蛋白-3的缺乏。然而，这些突变导致小窝蛋白-3缺乏和肌肉细胞变性的分子机制仍然是难以捉摸的。在这里，我们产生了转基因小鼠表达的Pro 104 Leu突变小窝蛋白-3。他们表现出严重的肌病伴随着肌膜中小窝蛋白-3的缺乏，表明突变小窝蛋白-3的显性负效应。有趣的是，我们发现他们的骨骼肌中nNOS活性大大增加，我们认为这可能在小窝蛋白-3的肌纤维变性中发挥作用。