Herbst Ruth, Iskratsch Thomas, Unger Ewald, Bittner Reginald E
Center for Brain Research, Medical University of Vienna, Vienna, Austria.
Neuromuscul Disord. 2009 May;19(5):366-78. doi: 10.1016/j.nmd.2009.02.011. Epub 2009 Apr 5.
Mice deficient in the glycosyltransferase Large are characterized by severe muscle and central nervous system abnormalities. In this study, we show that the formation and maintenance of neuromuscular junctions in Large(myd) mice are greatly compromised. Neuromuscular junctions are not confined to the muscle endplate zone but are widely spread and are frequently accompanied by exuberant nerve sprouting. Nerve terminals are highly fragmented and binding of alpha-bungarotoxin to postsynaptic acetylcholine receptors (AChRs) is greatly reduced. In vitro, Large(myd) myotubes are responsive to agrin but produce aberrant AChR clusters, which are larger in area and less densely packed with AChRs. In addition, AChR expression on the cell surface is diminished suggesting that AChR assembly or transport is defective. These results together with the finding that O-linked glycosylation at neuromuscular junctions of Large(myd) mice is compromised indicate that the action of Large is necessary for proper neuromuscular junction development.
缺乏糖基转移酶Large的小鼠表现出严重的肌肉和中枢神经系统异常。在本研究中，我们发现Large(myd)小鼠神经肌肉接头的形成和维持受到极大损害。神经肌肉接头不限于肌肉终板区，而是广泛分布，并经常伴有旺盛的神经芽生。神经末梢高度碎片化，α-银环蛇毒素与突触后乙酰胆碱受体（AChRs）的结合大大减少。在体外，Large(myd)肌管对聚集蛋白有反应，但产生异常的AChR簇，其面积更大且AChRs的密集程度更低。此外，细胞表面的AChR表达减少，表明AChR组装或运输存在缺陷。这些结果以及Large(myd)小鼠神经肌肉接头处O-连接糖基化受损的发现表明，Large的作用对于神经肌肉接头的正常发育是必需的。
