Taverna D, Disatnik M H, Rayburn H, Bronson R T, Yang J, Rando T A, Hynes R O
Howard Hughes Medical Institute and Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
J Cell Biol. 1998 Nov 2;143(3):849-59. doi: 10.1083/jcb.143.3.849.
alpha5-deficient mice die early in embryogenesis (). To study the functions of alpha5 integrin later in mouse embryogenesis and during adult life we generated alpha5 -/-;+/+ chimeric mice. These animals contain alpha5-negative and positive cells randomly distributed. Analysis of the chimerism by glucose- 6-phosphate isomerase (GPI) assay revealed that alpha5 -/- cells contributed to all the tissues analyzed. High contributions were observed in the skeletal muscle. The perinatal survival of the mutant chimeras was lower than for the controls, however the subsequent life span of the survivors was only slightly reduced compared with controls (). Histological analysis of alpha5 -/-;+/+ mice from late embryogenesis to adult life revealed an alteration in the skeletal muscle structure resembling a typical muscle dystrophy. Giant fibers, increased numbers of nuclei per fiber with altered position and size, vacuoli and signs of muscle degeneration-regeneration were observed in head, thorax and limb muscles. Electron microscopy showed an increase in the number of mitochondria in some muscle fibers of the mutant mice. Increased apoptosis and immunoreactivity for tenascin-C were observed in mutant muscle fibers. All the alterations were already visible at late stages of embryogenesis. The number of altered muscle fibers varied in different animals and muscles and was often increased in high percentage chimeric animals. Differentiation of alpha5 -/- ES cells or myoblasts showed that in vitro differentiation into myotubes was achieved normally. However proper adhesion and survival of myoblasts on fibronectin was impaired. Our data suggest that a novel form of muscle dystrophy in mice is alpha5-integrin-dependent.
α5 基因缺陷型小鼠在胚胎发育早期死亡（）。为了研究α5 整合素在小鼠胚胎发育后期及成年期的功能，我们构建了α5 -/-;+/+ 嵌合小鼠。这些动物体内α5 阴性和阳性细胞随机分布。通过葡萄糖 -6- 磷酸异构酶（GPI）检测分析嵌合情况发现，α5 -/- 细胞参与了所有分析的组织。在骨骼肌中观察到较高的嵌合率。突变嵌合体的围产期存活率低于对照组，然而，存活者随后的寿命与对照组相比仅略有缩短（）。对从胚胎发育后期到成年期的α5 -/-;+/+ 小鼠进行组织学分析发现，骨骼肌结构发生改变，类似于典型的肌肉营养不良。在头部、胸部和四肢肌肉中观察到巨大纤维、每根纤维中核数量增加且位置和大小改变、空泡以及肌肉变性 - 再生的迹象。电子显微镜显示，突变小鼠的一些肌肉纤维中线粒体数量增加。在突变肌肉纤维中观察到凋亡增加和肌腱蛋白 -C 的免疫反应性增强。所有这些改变在胚胎发育后期就已可见。不同动物和肌肉中改变的肌肉纤维数量各不相同，在高比例嵌合动物中通常会增加。α5 -/- 胚胎干细胞或成肌细胞的分化表明，体外正常分化为肌管。然而，成肌细胞在纤连蛋白上的正常黏附和存活受到损害。我们的数据表明，小鼠中一种新型的肌肉营养不良与α5 整合素有关。
