Neuromuscular junction defects in mice with mutation of dynein heavy chain 1.
Neuromuscular junction defects in mice with mutation of dynein heavy chain 1.
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DOI：
10.1371/journal.pone.0016753
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发表时间：
2011-02-04
期刊：
影响因子：
3.7
通讯作者：
Segal, Rosalind A
中科院分区：
文献类型：
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作者：
Courchesne, Stephanie L;Pazyra-Murphy, Maria F;Segal, Rosalind A
轴突运输的中断与广泛的神经退行性疾病有关。抽筋1型（Cra1/+）和奇角腿型（Loa/+）小鼠，其动力蛋白重链1基因（编码逆行运动蛋白动力蛋白的atp酶）发生亚形态突变，最初报道表现为迟发性运动神经元疾病。随后，相互矛盾的报告表明，没有运动神经元损失的感觉神经元疾病是Cra1/+和Loa/+小鼠表型的基础。在这里，我们介绍了Cra1/+小鼠的行为和解剖分析。我们发现Cra1/+小鼠表现出早发性、稳定的行为缺陷，包括后肢姿势异常和握力下降。这些缺陷不会持续到24个月大。在小鼠表现出明显症状的年龄，未观察到原发性运动神经元或背根神经节感觉神经元的显著损失。相反，神经肌肉连接的复杂性降低了。这些结果表明，Cra1/+小鼠动力蛋白功能的破坏导致神经肌肉连接形态异常。行为缺陷的时间过程以及神经肌肉连接形态缺陷的性质表明，Cra1/+小鼠动力蛋白功能的破坏导致突触组装或稳定的发育缺陷。
Disruptions in axonal transport have been implicated in a wide range of neurodegenerative diseases. Cramping 1 (Cra1/+) and Legs at odd angles (Loa/+) mice, with hypomorphic mutations in the dynein heavy chain 1 gene, which encodes the ATPase of the retrograde motor protein dynein, were originally reported to exhibit late onset motor neuron disease. Subsequent, conflicting reports suggested that sensory neuron disease without motor neuron loss underlies the phenotypes of Cra1/+ and Loa/+ mice. Here, we present behavioral and anatomical analyses of Cra1/+ mice. We demonstrate that Cra1/+ mice exhibit early onset, stable behavioral deficits, including abnormal hindlimb posturing and decreased grip strength. These deficits do not progress through 24 months of age. No significant loss of primary motor neurons or dorsal root ganglia sensory neurons was observed at ages where the mice exhibited clear symptomatology. Instead, there is a decrease in complexity of neuromuscular junctions. These results indicate that disruption of dynein function in Cra1/+ mice results in abnormal morphology of neuromuscular junctions. The time course of behavioral deficits, as well as the nature of the morphological defects in neuromuscular junctions, suggests that disruption of dynein function in Cra1/+ mice causes a developmental defect in synapse assembly or stabilization.