Characterization of a muscle-specific enhancer in human MuSK promoter reveals the essential role of myogenin in controlling activity-dependent gene regulation
Characterization of a muscle-specific enhancer in human MuSK promoter reveals the essential role of myogenin in controlling activity-dependent gene regulation
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DOI：
10.1074/jbc.m511317200
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发表时间：
2006-02-17
影响因子：
4.8
通讯作者：
Goldman, D
中科院分区：
文献类型：
--
作者：
Tang, HB;Veldman, MB;Goldman, D
神经肌肉突触发生是由运动神经元聚集蛋白的释放和突触后膜中受体酪氨酸激酶MuSK的激活启动的。MuSK基因的表达受神经源性聚集蛋白和肌肉活动的调节。聚集蛋白通过激活终板相关肌核中的GABP（α β）转录因子刺激突触特异性MuSK基因表达。相比之下，肌肉活动调节MuSK基因表达的机制尚不清楚。我们报告一个60 bp的MuSK增强子，赋予肌肉分化，细胞内钙的变化，肌肉活动的启动子调节。在这个增强子中，我们确定了一个对这种调节至关重要的E-box。这个E-box与肌细胞生成素结合，我们发现肌细胞生成素不仅是MuSK所必需的，而且是肌肉活动调节nAChR基因所必需的。令人惊讶的是，相同的E-box功能在体内介导肌肉特异性和分化依赖的基因诱导在斑马鱼，提示突触蛋白基因表达的调节进化保守的机制。
Neuromuscular synaptogenesis is initiated by the release of agrin from motor neurons and the activation of the receptor tyrosine kinase, MuSK, in the postsynaptic membrane. MuSK gene expression is regulated by nerve-derived agrin and muscle activity. Agrin stimulates synapse-specific MuSK gene expression by activating GABP(alpha beta) transcription factors in endplate-associated myonuclei. In contrast, the mechanism by which muscle activity regulates MuSK gene expression is not known. We report on a 60-bp MuSK enhancer that confers promoter regulation by muscle differentiation, changes in intracellular calcium, and muscle activity. Within this enhancer, we identified a single E-box that is essential for this regulation. This E-box binds myogenin, and we showed that myogenin is necessary for not only MuSK but also nAChR gene regulation by muscle activity. Surprisingly, the same E-box functions in vivo to mediate muscle-specific and differentiation-dependent gene induction in zebrafish, suggesting an evolutionary conserved mechanism of regulation of synaptic protein gene expression.