Zebrafish as a model for caveolin-associated muscle disease;: caveolin-3 is required for myofibril organization and muscle cell patterning
Zebrafish as a model for caveolin-associated muscle disease;: caveolin-3 is required for myofibril organization and muscle cell patterning
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DOI：
10.1093/hmg/ddi179
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发表时间：
2005-07-01
影响因子：
3.5
通讯作者：
Parton, RG
中科院分区：
文献类型：
--
作者：
Nixon, SJ;Wegner, J;Parton, RG
小窝是许多动物细胞的丰富特征。然而，小窝的确切功能仍不清楚。我们已经使用斑马鱼，Danio rerio，作为一个系统来了解肌膜小窝功能，专注于肌肉特异性小窝蛋白，小窝蛋白-3（Cav 3）。我们已经在斑马鱼中鉴定出caveolin-1（alpha和beta），caveolin-2和Cav 3。斑马鱼Cav 3与人CAV 3具有72%的同一性，并且在人肌肉疾病中改变的氨基酸在斑马鱼蛋白中是保守的。在胚胎发育过程中，cav 3的表达是明显的早期分割阶段的第一个分化的肌肉前体，近轴细胞和稍晚在脊索。cav 3的表达出现在体节在中期分割阶段，然后在胸鳍和面部肌肉。Cav 3和小窝位于沿着晚期胚胎肌纤维的整个肌膜，而β-肌营养不良蛋白聚糖仅限于肌纤维末端。Cav 3表达的下调导致肌肉异常和不协调运动。离体肌纤维的超微结构分析显示成肌细胞融合缺陷和肌原纤维和膜系统紊乱。表达相当于人肌营养不良症突变体CAV 3 P104 L的斑马鱼导致肌肉分化严重中断。此外，Cav 3的敲低导致eng 1a表达的显著上调，导致脊索附近的肌肉先驱样细胞数量增加。这些研究为Cav 3在肌肉发育中的作用提供了新的见解，并证明了其对正确的细胞内组织和成肌细胞融合的要求。
Caveolae are an abundant feature of many animal cells. However, the exact function of caveolae remains unclear. We have used the zebrafish, Danio rerio, as a system to understand caveolae function focusing on the muscle-specific caveolar protein, caveolin-3 (Cav3). We have identified caveolin-1 (alpha and beta), caveolin-2 and Cav3 in the zebrafish. Zebrafish Cav3 has 72% identity to human CAV3, and the amino acids altered in human muscle diseases are conserved in the zebrafish protein. During embryonic development, cav3 expression is apparent by early segmentation stages in the first differentiating muscle precursors, the adaxial cells and slightly later in the notochord. cav3 expression appears in the somites during mid-segmentation stages and then later in the pectoral fins and facial muscles. Cav3 and caveolae are located along the entire sarcolemma of late stage embryonic muscle fibers, whereas beta-dystroglycan is restricted to the muscle fiber ends. Down-regulation of Cav3 expression causes gross muscle abnormalities and uncoordinated movement. Ultrastructural analysis of isolated muscle fibers reveals defects in myoblast fusion and disorganized myofibril and membrane systems. Expression of the zebrafish equivalent to a human muscular dystrophy mutant, CAV3P104L, causes severe disruption of muscle differentiation. In addition, knockdown of Cav3 resulted in a dramatic up-regulation of eng1a expression resulting in an increase in the number of muscle pioneer-like cells adjacent to the notochord. These studies provide new insights into the role of Cav3 in muscle development and demonstrate its requirement for correct intracellular organization and myoblast fusion.