Dysregulation of nuclear receptor COUP-TFII impairs skeletal muscle development.
Dysregulation of nuclear receptor COUP-TFII impairs skeletal muscle development.
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DOI：
10.1038/s41598-017-03475-5
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发表时间：
2017-06-09
影响因子：
4.6
通讯作者：
Tsai MJ
中科院分区：
文献类型：
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作者：
Lee HJ;Kao CY;Lin SC;Xu M;Xie X;Tsai SY;Tsai MJ
鸡卵清蛋白上游启动子转录因子 II (COUP-TFII) 已被证明可以在体外抑制肌生成和骨骼肌代谢。然而，其在肌肉发育中的确切作用和体内功能尚未明确定义。 COUP-TFII 蛋白表达水平在未分化祖细胞中较高，并在分化过程中逐渐下降，提出了一个重要问题：适当的肌细胞分化是否需要下调 COUP-TFII 表达。在这项研究中，我们建立了一个在肌原细胞中异位表达 COUP-TFII 的小鼠模型，以在肌发生过程中维持 COUP-TFII 活性，并发现 COUP-TFII 活性升高导致骨骼肌发育效率低下。通过体外细胞培养和体内小鼠模型，我们发现 COUP-TFII 通过抑制成肌细胞融合来阻碍肌原性发育。从机制上讲，低效的肌肉细胞融合与 Npnt、Itgb1D 和 Cav3（对细胞间融合很重要的基因）的转录抑制密切相关。我们进一步证明，COUP-TFII 还可以减少粘着斑激酶 (FAK) 的激活，FAK 是一种整合素下游调节因子，对于融合过程至关重要。总的来说，我们的研究强调了下调 COUP-TFII 信号传导以诱导对成肌细胞融合至关重要的因子的重要性。
Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) has been shown to inhibit myogenesis and skeletal muscle metabolism in vitro. However, its precise role and in vivo function in muscle development has yet to be clearly defined. COUP-TFII protein expression level is high in undifferentiated progenitors and gradually declines during differentiation, raising an important question of whether downregulation of COUP-TFII expression is required for proper muscle cell differentiation. In this study, we generated a mouse model ectopically expressing COUP-TFII in myogenic precursors to maintain COUP-TFII activity during myogenesis and found that elevated COUP-TFII activity resulted in inefficient skeletal muscle development. Using in vitro cell culture and in vivo mouse models, we showed that COUP-TFII hinders myogenic development by repressing myoblast fusion. Mechanistically, the inefficient muscle cell fusion correlates well with the transcriptional repression of Npnt, Itgb1D and Cav3, genes important for cell-cell fusion. We further demonstrated that COUP-TFII also reduces the activation of focal adhesion kinase (FAK), an integrin downstream regulator which is essential for fusion process. Collectively, our studies highlight the importance of down-regulation of COUP-TFII signaling to allow for the induction of factors crucial for myoblast fusion.