p38 mitogen-activated protein kinase activity commits embryonic stem cells to either neurogenesis or cardiomyogenesis
p38 mitogen-activated protein kinase activity commits embryonic stem cells to either neurogenesis or cardiomyogenesis
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DOI：
10.1634/stemcells.2005-0398
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发表时间：
2006-05-01
期刊：
影响因子：
5.2
通讯作者：
Binetruy, Bernard
中科院分区：
文献类型：
--
作者：
Aouadi, Myriam;Bost, Frederic;Binetruy, Bernard
小鼠胚胎干细胞（ES）可以在体外分化为多种细胞类型，包括心肌细胞和神经元。这一过程受到强效形态形成因子维甲酸（RA）的严格控制。在浓度为10(-7)M时，RA诱导ES细胞分化为神经元，相反，抑制心肌生成。我们发现p38丝裂原活化蛋白激酶（p38MAPK）活性在胚胎干细胞分化的第3天至第5天自发达到峰值，而RA完全抑制了这一活性峰值。与需要RA治疗的野生型细胞相比，p38 α (-/-) ES细胞自发分化为神经元，不形成心肌细胞。此外，一种特殊的抑制剂PD169316抑制p38MAPK活性的峰值，使ES细胞进入神经元谱系并阻断心肌形成。通过遗传和生化方法，我们证明，在两种不同的胚胎干细胞系中，p38MAPK活性的控制构成了一个早期开关，使胚胎干细胞进入神经发生（p38关闭）或心肌发生（p38打开）。
Mouse embryonic stem (ES) cells can be differentiated, in vitro into a variety of cell types including cardiac cells and neurons. This process is strictly controlled by the potent morphogen retinoic acid (RA). At a concentration of 10(-7) M, RA induces ES cell differentiation into neurons and, conversely, inhibits cardiomyogenesis. We found that p38 mitogen-activated protein kinase (p38MAPK) activity peaked spontaneously, between day 3 and day 5, during ES cell differentiation and that RA completely inhibited this peak of activity. In contrast to wild-type cells, which required RA treatment, p38 alpha(-/-) ES cells differentiated spontaneously into neurons and did not form cardiomyocytes. Moreover, inhibition of the peak of p38MAPK activity by a specific inhibitor, PD169316, committed ES cells into the neuronal lineage and blocked cardiomyogenesis. By genetic and biochemical approaches, we demonstrate that, in two different ES cell lines, the control of p38MAPK activity constitutes an early switch, committing ES cells into either neurogenesis (p38 off) or cardiomyogenesis (p38 on).