p38 Mitogen-activated protein kinase controls a switch between cardiomyocyte and neuronal commitment of murine embryonic stem cells by activating myocyte enhancer factor 2C-dependent bone morphogenetic protein 2 transcription.
p38 Mitogen-activated protein kinase controls a switch between cardiomyocyte and neuronal commitment of murine embryonic stem cells by activating myocyte enhancer factor 2C-dependent bone morphogenetic protein 2 transcription.
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DOI：
10.1089/scd.2010.0066
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发表时间：
2010-04
影响因子：
4
通讯作者：
Jinzhan Wu;Junko Kubota;J. Hirayama;Y. Nagai;S. Nishina;T. Yokoi;Yoichi Asaoka;Jungwon Seo;Nao Shimizu;H. Kajiho;Takashi Watanabe;N. Azuma;T. Katada;H. Nishina
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文献类型：
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作者：
Jinzhan Wu;Junko Kubota;J. Hirayama;Y. Nagai;S. Nishina;T. Yokoi;Yoichi Asaoka;Jungwon Seo;Nao Shimizu;H. Kajiho;Takashi Watanabe;N. Azuma;T. Katada;H. Nishina
许多研究已经表明，可以使用培养条件来指导小鼠胚胎干（ES）细胞分化为多种细胞类型，包括心肌细胞和神经元。然而，控制ES细胞谱系定型决定的分子机制仍然知之甚少。在这项研究中，我们研究了3种主要的丝裂原活化蛋白激酶（MAPK：细胞外信号调节激酶，c-Jun N-末端激酶和p38）在ES细胞谱系定型中的作用，并表明p38 MAPK特异性抑制剂SB 203580阻断了ES细胞自发分化为心肌细胞，而是诱导这些ES细胞分化为神经元。胚状体培养第3天和第4天之间的强p38 MAPK活性对于ES细胞的心肌发生是至关重要的，此时特异性抑制p38 MAPK活性导致ES细胞分化为神经元而不是心肌细胞。在分子水平上，抑制p38 MAPK活性抑制BMP-2 mRNA的表达，而用骨形态发生蛋白2（BMP-2）处理ES细胞抑制SB 203580诱导的神经发生。此外，荧光素酶报告基因测定和染色质免疫沉淀实验表明，BMP-2在ES细胞中的表达直接受转录因子肌细胞增强因子2C（一种众所周知的p38 MAPK底物）的调节。我们的研究结果揭示了ES细胞中p38 MAPK活性驱动其优先分化为心肌细胞的分子机制，以及这些细胞可能发育为神经元的条件。
Many studies have shown that it is possible to use culture conditions to direct the differentiation of murine embryonic stem (ES) cells into a variety of cell types, including cardiomyocytes and neurons. However, the molecular mechanisms that control lineage commitment decisions by ES cells remain poorly understood. In this study, we investigated the role of the 3 major mitogen-activated protein kinases (MAPKs: extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38) in ES cell lineage commitment and showed that the p38 MAPK-specific inhibitor SB203580 blocks the spontaneous differentiation of ES cells into cardiomyocytes and instead induces the differentiation of these ES cells into neurons. Robust p38 MAPK activity between embryoid body culture days 3 and 4 is crucial for cardiomyogenesis of ES cells, and specific inhibition of p38 MAPK activity at this time results in ES cell differentiation into neurons rather than cardiomyocytes. At the molecular level, inhibition of p38 MAPK activity suppresses the expression of bmp-2 mRNA, whereas treatment of ES cells with bone morphogenetic protein 2 (BMP-2) inhibits the neurogenesis induced by SB203580. Further, luciferase reporter assays and chromatin immunoprecipitation experiments showed that BMP-2 expression in ES cells is regulated directly by the transcription factor myocyte enhancer factor 2C, a well-known substrate of p38 MAPK. Our findings reveal the molecular mechanism by which p38 MAPK activity in ES cells drives their commitment to differentiate preferentially into cardiomyocytes, and the conditions under which these same cells might develop into neurons.