Defective Neuromuscular Junction Organization and Postnatal Myogenesis in Mice With Severe Spinal Muscular Atrophy
Defective Neuromuscular Junction Organization and Postnatal Myogenesis in Mice With Severe Spinal Muscular Atrophy
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DOI：
10.1097/nen.0b013e31821cbd8b
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发表时间：
2011-06-01
影响因子：
3.2
通讯作者：
Esquerda, Josep E.
中科院分区：
文献类型：
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作者：
Dachs, Elisabet;Hereu, Marta;Esquerda, Josep E.
对Smn（-/-）进行详细的病理分析；SMN2（+/+）小鼠作为人类I型脊髓性肌萎缩症（SMA）的小鼠模型。我们提供了有关脊髓，神经肌肉连接和肌肉细胞以及免疫系统器官变化的新数据。用共聚焦显微镜分析了10种突触蛋白在三维重建神经肌肉连接中的表达。除了突触后占用缺陷外，在部分（但不是全部）骨骼肌的突触前运动末端，降钙素基因相关肽和Rab3A也明显减少。电镜观察到突触前神经末梢组织缺陷。此外，还观察到肌肉细胞退行性改变，产后肌肉生长缺陷，肌肉卫星细胞凋亡突出。所有这些变化都发生在脊髓运动神经元大量丧失的情况下。另一方面，新生SMA小鼠腹角的星形胶质细胞增加，而小胶质细胞没有增加。在骨骼肌中，间质巨噬细胞密度显著降低，单核细胞趋化蛋白-1下调。这些发现提出了关于肌细胞缺陷对SMA表型的主要贡献的问题。
A detailed pathologic analysis was performed on Smn(-/-);SMN2(+/+) mice as a mouse model for human type I spinal muscular atrophy (SMA). We provide new data concerning changes in the spinal cord, neuromuscular junctions and muscle cells, and in the organs of the immune system. The expression of 10 synaptic proteins was analyzed in 3-dimensionally reconstructed neuromuscular junctions by confocal microscopy. In addition to defects in postsynaptic occupancy, there was a marked reduction in calcitonin gene-related peptide and Rab3A in the presynaptic motor terminals of some, but not all, of the skeletal muscles analyzed. Defects in the organization of presynaptic nerve terminals were also detected by electron microscopy. Moreover, degenerative changes in muscle cells, defective postnatal muscle growth, and prominent muscle satellite cell apoptosis were also observed. All of these changes occurred in the absence of massive loss of spinal cord motoneurons. On the other hand, astroglia, but not microglia, increased in the ventral horn of newborn SMA mice. In skeletal muscles, the density of interstitial macrophages was significantly reduced, and monocyte chemotactic protein-1 was downregulated. These findings raise questions regarding the primary contribution of a muscle cell defect to the SMA phenotype.