8月19日，《神经科学杂志》（The Journal of Neuroscience）发表了中国科学院上海生命科学研究院神经科学研究所的研究成果：“NFkappaB控制乙酰胆碱受体在神经肌肉接头的聚集”。该项工作是由王佳和伏秀清等在罗振革研究员指导下完成的。
转录因子NFkB在炎症和免疫反应中起重要的调控作用，但在神经系统的功能尚不清楚。罗振革研究员带领的突触信号研究组分析了NFkB在神经肌肉接头突触形成中的作用。首先，他们发现NFkB的p65亚基在神经肌肉接头部位存在富集。在培养的肌肉细胞上调p65的表达促进了乙酰胆碱受体的聚集。相反，下调p65的表达或抑制NFkB的功能抑制了乙酰胆碱受体聚集体的形成。在骨骼肌中特异地敲除p65基因可导致小鼠神经肌肉接头的发育异常。
通过分析p65的作用机制，他们发现p65对突触部位脚手架蛋白Rapsyn的表达起重要的调节作用。因此，炎性因子NFkB介导的转录调控在神经肌肉接头突触形成中发挥重要的作用。
该工作得到了中国科学院、国家科技部、自然科学基金委及上海市科委的资助。
推荐原文出处：
The Journal of Neuroscience doi:10.1523/JNEUROSCI.2118-10.2010
Nuclear Factor B Controls Acetylcholine Receptor Clustering at the Neuromuscular Junction
Jia Wang, * Xiu-Qing Fu, * Wen-Liang Lei, Tong Wang, Ai-Li Sheng, and Zhen-Ge Luo
Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
At the vertebrate neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is stimulated by motor neuron-derived glycoprotein Agrin and requires a number of intracellular signal or structural proteins, including AChR-associated scaffold protein Rapsyn. Here, we report a role of nuclear factor B (NF-B), a well known transcription factor involved in a variety of immune responses, in regulating AChR clustering at the NMJ. We found that downregulating the expression of RelA/p65 subunit of NF-B or inhibiting NF-B activity by overexpression of mutated form of IB (inhibitor B), which is resistant to proteolytic degradation and thus constitutively keeps NF-B inactive in the cytoplasma, impeded the formation of AChR clusters in cultured C2C12 muscle cells stimulated by Agrin. In contrast, overexpression of RelA/p65 promoted AChR clustering. Furthermore, we investigated the mechanism by which NF-B regulates AChR clustering. Interestingly, we found that downregulating the expression of RelA/p65 caused a marked reduction in the protein and mRNA level of Rapsyn and upregulation of RelA/p65 enhanced Rapsyn promoter activity. Mutation of NF-B binding site on Rapsyn promoter prevented responsiveness to RelA/p65 regulation. Moreover, forced expression of Rapsyn in RelA/p65 downregulated muscle cells partially rescued AChR clusters, suggesting that NF-B regulates AChR clustering, at least partially through the transcriptional regulation of Rapsyn. In line with this notion, genetic ablation of RelA/p65 selectively in the skeletal muscle caused a reduction of AChR density at the NMJ and a decrease in the level of Rapsyn. Thus, NF-B signaling controls AChR clustering through transcriptional regulation of synaptic protein Rapsyn.
