ColQ Controls Postsynaptic Differentiation at the Neuromuscular Junction
ColQ Controls Postsynaptic Differentiation at the Neuromuscular Junction
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DOI：
10.1523/jneurosci.4374-09.2010
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发表时间：
2010-01-06
影响因子：
5.3
通讯作者：
Legay, Claire
中科院分区：
文献类型：
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作者：
Sigoillot, Severine M.;Bourgeois, Francine;Legay, Claire
colagenq （ColQ）通过在细胞外基质（ECM）中锚定和积累乙酰胆碱酯酶（AChE），在脊椎动物神经肌肉连接（NMJs）中发挥重要的结构作用。此外，ColQ与perlecan/ dysstrodglycan和肌肉特异性受体酪氨酸激酶（MuSK）相互作用，这是NMJ形成的关键分子。在rapsyn介导的过程中，MuSK促进乙酰胆碱受体（AChR）聚集，rapsyn是一种细胞质蛋白，刺激AChR聚集并调节突触基因转录。在这里，我们通过比较野生型和ColQ缺陷型肌肉细胞在培养和NMJ下突触蛋白的聚类和表达来研究ColQ的调节作用。我们首先表明，在体外和体内没有ColQ的情况下，AChR簇更小，排列更密集。其次，我们发现与achr和rapsyn一样，培养细胞中的MuSK mRNA水平升高，而缺乏ColQ的肌肉中则没有。然而，在体外和体内，膜结合的MuSK都减少了，这表明ColQ控制着肌膜上MuSK的分选或稳定。与此相一致，我们的数据表明，在缺乏ColQ的情况下，MuSK信号通路的激活会发生改变，导致(1)AChR聚类和/或β -AChR亚基磷酸化受到干扰；(2)由于缺乏ColQ-MuSK相互作用，AChR mRNA水平发生改变。综上所述，我们的研究结果表明，ColQ除了具有结构作用外，还通过与MuSK的相互作用控制AChR聚类和突触基因表达，在突触中具有重要的调节功能。
CollagenQ (ColQ) plays an important structural role at vertebrate neuromuscular junctions (NMJs) by anchoring and accumulating acetylcholinesterase (AChE) in the extracellular matrix (ECM). Moreover, ColQ interacts with perlecan/dystroglycan and the muscle-specific receptor tyrosine kinase (MuSK), key molecules in the NMJ formation. MuSK promotes acetylcholine receptor (AChR) clustering in a process mediated by rapsyn, a cytoplasmic protein that stimulates AChR packing in clusters and regulates synaptic gene transcription. Here, we investigated a regulatory role for ColQ by comparing the clustering and expression of synaptic proteins in wild type and ColQ-deficient muscle cells in culture and at NMJ. We show first that AChR clusters are smaller and more densely packed in the absence of ColQ both in vitro and in vivo. Second, we find that like AChRs and rapsyn, MuSK mRNA levels are increased in cultured cells but not in muscles lacking ColQ. However, membrane-bound MuSK is decreased both in vitro and in vivo suggesting that ColQ controls MuSK sorting or stabilization in the muscle membrane. In line with this, our data show that activation of the MuSK signaling pathway is altered in the absence of ColQ leading to (1) perturbation of AChR clustering and/or beta-AChR subunit phosphorylation and (2) modifications of AChR mRNA level due to the lack of ColQ-MuSK interaction. Together, our results demonstrate that ColQ, in addition to its structural role, has important regulatory functions at the synapse by controlling AChR clustering and synaptic gene expression through its interaction with MuSK.