Survival motor neuron (SMN) protein: role in neurite outgrowth and neuromuscular maturation during neuronal differentiation and development
Survival motor neuron (SMN) protein: role in neurite outgrowth and neuromuscular maturation during neuronal differentiation and development
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DOI：
10.1093/hmg/11.14.1605
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发表时间：
2002-07-01
影响因子：
3.5
通讯作者：
Simard, LR
中科院分区：
文献类型：
--
作者：
Fan, L;Simard, LR
儿童脊髓性肌萎缩症（SMA）是一种常见的神经肌肉疾病，其原因是全长运动神经元存活蛋白（SMN）缺失或缺陷。临床研究和动物模型表明，SMA是神经肌肉相互作用的发育缺陷;然而，SMN在这一过程中的作用仍不清楚。在本研究中，我们已经确定了亚细胞定位的SMN维甲酸诱导的神经元分化的小鼠胚胎畸胎瘤P19细胞，以及在骨骼肌的神经肌肉成熟的关键时期。我们证明，第一次，SMN积累在生长锥和丝状伪足样结构的神经元和神经胶质样细胞，确定SMN作为一个新的生长锥标记。事实上，SMN存在于神经突生长的前沿，表明SMN可能在此过程中发挥作用。此外，在出生后的前2周内，在骨骼肌细胞质内检测到SMN为小的点状颗粒，但其数量在P6时达到峰值。在整个出生后检查期间，观察到神经肌肉接头中的强烈SMN染色。总之，这些结果表明，SMN可能确实履行神经元和肌肉特异性功能，提供了一个更合理的机制，解释运动神经元变性和相关的失神经萎缩的骨骼肌SMA。原发性SMA病理学最可能起始于外周轴突--神经突生长和/或神经肌肉成熟不足的结果。
Childhood spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by absent or deficient full-length survival motor neuron (SMN) protein. Clinical studies and animal models suggest that SMA is a developmental defect in neuromuscular interaction; however, the role of SMN in this process remains unclear. In the present study, we have determined the subcellular localization of SMN during retinoic-acid-induced neuronal differentiation of mouse embryonal teratocarcinoma P19 cells as well as in skeletal muscle during the critical period of neuromuscular maturation. We demonstrate, for the first time, SMN accumulation in growth-cone- and filopodia-like structures in both neuronal- and glial-like cells, identifying SMN as a new growth cone marker. Indeed, SMN was present at the leading edge of neurite outgrowths, suggesting that SMN may play a role in this process. In addition, SMN was detected as small dot-like particles within the cytoplasm of skeletal muscle during the first 2 weeks after birth, but their number peaked by P6. Intense SMN staining in neuromuscular junctions was observed throughout the entire postnatal period examined. Taken together, these results suggest that SMN may indeed fulfill neuronal- and muscle-specific functions, providing a more plausible mechanism explaining motor neuron degeneration and associated denervation atrophy of skeletal muscles in SMA. The primary SMA pathology most likely initiates in the peripheral axon - the result of deficient neurite outgrowth and/or neuromuscular maturation.