Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses
Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses
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DOI：
10.1038/15519
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发表时间：
1999-11-01
期刊：
影响因子：
30.8
通讯作者：
Carbonetto, S
中科院分区：
文献类型：
--
作者：
Côté, PD;Moukhles, H;Carbonetto, S
肌营养不良蛋白基因1（DMD）和编码几种肌营养不良蛋白相关蛋白的基因突变导致杜氏肌营养不良症和其他形式的肌营养不良症2。α-肌营养不良聚糖（Dg）与每个肌纤维周围的基底膜中的层粘连蛋白结合，并与β-Dg（一种跨膜蛋白）对接，后者进而与质膜下细胞骨架中的肌营养不良蛋白或肌营养不良蛋白相互作用。α-和β-Dgs被认为形成了从基底膜延伸到细胞内细胞骨架的更大蛋白质复合物的功能核心，其作为肌膜完整性所必需的超结构2。DGS还涉及骨骼肌上乙酰胆碱受体（AChR）的突触密度的形成3，4。在这里，我们报告说，嵌合体小鼠与ES细胞靶向两个Dg等位基因的骨骼肌基本上没有Dgs和发展的渐进性肌肉病理学的变化，标志着人类肌肉营养不良。此外，在这些小鼠中，许多神经肌肉接头被破坏。基底膜的超微结构和层粘连蛋白的沉积在其中，然而，出现在DG缺乏的肌肉不受影响。我们的结论是，DGS是必要的肌纤维的生存和突触分化或稳定性，但不是肌肉基底膜的形成，DGS可能有一个以上的纯粹的结构功能，在维持肌肉的完整性。
Mutations in the dystrophin gene 1 (DMD) and in genes encoding several dystrophin-associated proteins result in Duchenne and other forms of muscular dystrophy 2. α-Dystroglycan (Dg) binds to laminins in the basement membrane surrounding each myofibre and docks with β-Dg, a transmembrane protein, which in turn interacts with dystrophin or utrophin in the subplasmalemmal cytoskeleton. α-and β-Dgs are thought to form the functional core of a larger complex of proteins extending from the basement membrane to the intracellular cytoskeleton, which serves as a superstructure necessary for sarcolemmal integrity 2. Dgs have also been implicated in the formation of synaptic densities of acetylcholine receptors (AChRs) on skeletal muscle 3, 4. Here we report that chimaeric mice generated with ES cells targeted for both Dg alleles have skeletal muscles essentially devoid of Dgs and develop a progressive muscle pathology with changes emblematic of muscular dystrophies in humans. In addition, many neuromuscular junctions are disrupted in these mice. The ultrastructure of basement membranes and the deposition of laminin within them, however, appears unaffected in Dg-deficient muscles. We conclude that Dgs are necessary for myofibre survival and synapse differentiation or stability, but not for the formation of the muscle basement membrane, and that Dgs may have more than a purely structural function in maintaining muscle integrity.