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Abstract：
Cofilin, an actin severing protein, plays critical roles in muscle sarcomere addition and maintenance. Our previous work has shown Drosophila cofilin (DmCFL) knockdown causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy (NM) caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by DmCFL knockdown would impact other aspects of muscle development, and, thus, conducted an RNA sequencing analysis which unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL deficiency causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However, DmCFL knockdown results in mislocalization of glutamate receptors containing the GluRIIA subunit in more deteriorated muscles and neurotransmission strength is strongly impaired. These findings expand our understanding of cofilin\'s roles in muscle to include NMJ structural development and suggest that NMJ defects may contribute to NM pathophysiology.
摘要：
Cofilin,一种肌动蛋白切断蛋白，在肌肉肌节的添加和维持中起着至关重要的作用。我们先前的工作表明，果蝇cofilin（DmCFL）敲低会导致肌肉结构和功能逐渐恶化，并产生由cofilin突变引起的线虫肌病（NM）中可见的特征。我们假设DmCFL敲低对肌动蛋白细胞骨架动力学的破坏会影响肌肉发育的其他方面，and,因此，进行了RNA测序分析，该分析出乎意料地揭示了许多神经肌肉接头（NMJ）基因的上调表达。我们发现DmCFL在肌肉突触后区室中富集，并且DmCFL缺乏在发育后期观察到的肌节缺陷之前会导致该亚细胞结构域中的F-肌动蛋白解体。尽管NMJ基因表达发生变化,我们发现突触前Bruchpilot总活动区或突触后谷氨酸受体总水平无显著变化.然而,DmCFL敲低导致含有GluRIIA亚基的谷氨酸受体在更多恶化的肌肉中的错误定位，并且神经传递强度受到强烈损害。这些发现扩大了我们对cofilin在肌肉中的作用的理解，包括NMJ结构发育，并表明NMJ缺陷可能有助于NM病理生理学。
■Cofilin调节肌肉突触后肌动蛋白组织，结构维护,谷氨酸受体组成，果蝇线虫肌病模型中的神经肌肉接头功能。
■Cofilin调节肌肉突触后肌动蛋白组织，结构维护,谷氨酸受体组成，果蝇线虫肌病模型中的神经肌肉接头功能。
