Mayer U, Saher G, Fässler R, Bornemann A, Echtermeyer F, von der Mark H, Miosge N, Pöschl E, von der Mark K
Max-Planck-Institute for Biochemistry, Martinsried, Germany.
Nat Genet. 1997 Nov;17(3):318-23. doi: 10.1038/ng1197-318.
Integrin alpha 7 beta 1 is a specific cellular receptor for the basement membrane protein laminin-1 (refs 1,2), as well as for the laminin isoforms -2 and -4 (ref. 3). The alpha 7 subunit is expressed mainly in skeletal and cardiac muscle and has been suggested to be involved in differentiation and migration processes during myogenesis. Three cytoplasmic and two extracellular splice variants that have been described are developmentally regulated and expressed in different sites in the muscle. In adult muscle, the alpha 7A and alpha 7B subunits are concentrated in myotendinous junctions but can also be detected in neuromuscular junctions and along the sarcolemmal membrane. To study the potential involvement of alpha 7 integrin, during myogenesis and its role in muscle integrity and function, we generated a null allele of the alpha 7 gene (Itga7) in the germline of mice by homologous recombination in embryonic stem (ES) cells. Surprisingly, mice homozygous for the mutation are viable and fertile, indicating that the alpha 7 beta 1 integrin is not essential for myogenesis. However, histological analysis of skeletal muscle revealed typical symptoms of a progressive muscular dystrophy starting soon after birth, but with a distinct variability in different muscle types. The observed histopathological changes strongly indicate an impairment of function of the myotendinous junctions. These findings demonstrate that alpha 7 beta 1 integrin represents an indispensable linkage between the muscle fibre and the extracellular matrix that is independent of the dystrophin-dystroglycan complex-mediated interaction of the cytoskeleton with the muscle basement membrane.
整合素α7β1是基底膜蛋白层粘连蛋白-1（参考文献1,2）以及层粘连蛋白异构体-2和-4（参考文献3）的特异性细胞受体。α7亚基主要在骨骼肌和心肌中表达，有人认为它参与了肌发生过程中的分化和迁移过程。已描述的三种胞质和两种胞外剪接变体在发育过程中受到调控，并在肌肉的不同部位表达。在成年肌肉中，α7A和α7B亚基集中在肌腱连接部位，但在神经肌肉接头和沿肌膜也能检测到。为了研究α7整合素在肌发生过程中的潜在作用及其在肌肉完整性和功能中的作用，我们通过胚胎干细胞（ES）中的同源重组在小鼠生殖系中产生了α7基因（Itga7）的无效等位基因。令人惊讶的是，该突变的纯合子小鼠是存活且可育的，这表明α7β1整合素对肌发生不是必需的。然而，骨骼肌的组织学分析显示，出生后不久就开始出现进行性肌肉营养不良的典型症状，但不同肌肉类型的症状有明显差异。观察到的组织病理学变化强烈表明肌腱连接功能受损。这些发现表明，α7β1整合素代表了肌纤维与细胞外基质之间不可或缺的联系，这一联系独立于肌营养不良蛋白-肌营养不良聚糖复合物介导的细胞骨架与肌肉基底膜的相互作用。
