Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network
Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network
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DOI：
10.1242/dev.109678
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发表时间：
2014-10-01
期刊：
影响因子：
4.6
通讯作者：
Chazaud, Claire
中科院分区：
文献类型：
--
作者：
Bessonnard, Sylvain;De Mot, Laurane;Chazaud, Claire
在囊胚形成过程中，内细胞团 (ICM) 细胞分化为外胚层 (Epi) 或原始内胚层 (PrE) 细胞，分别用 Nanog 和 Gata6 标记，并以椒盐模式组织。先前在小鼠中的研究表明，在缺乏 Nanog 的情况下，所有 ICM 细胞都会采用 PrE 身份。此外，Fgf/RTK 通路的激活或阻断分别使细胞命运规范偏向于 PrE 或 Epi。我们发现，在没有 Gata6 的情况下，所有 ICM 细胞都采用 Epi 身份。此外，Gata6(+/-) 胚胎的分析揭示了剂量敏感的表型，PrE 特异性细胞较少。这些结果和之前的发现使得能够开发控制 ICM 分化为 Epi 或 PrE 细胞的调控网络动力学的数学模型。该模型描述了 Erk 信号传导以及 Nanog、Gata6、分泌的 Fgf4 和 Fgf 受体 2 浓度的时间动态。该模型能够概括在不同实验条件下观察到的大多数细胞行为，并为这些发育转变的动态提供统一的机制。该机制依赖于三种稳定状态（三态性）之间的共存，这三种状态分别对应于 ICM、Epi 和 PrE 细胞。总而言之，建模和实验结果揭示了 ICM 细胞命运规范的新特征，例如细胞子集初始诱导进入 Epi 在椒盐模式启动中的作用，或 Gata6(+/-) 胚胎中早熟的 Epi 规范。
During blastocyst formation, inner cell mass (ICM) cells differentiate into either epiblast (Epi) or primitive endoderm (PrE) cells, labeled by Nanog and Gata6, respectively, and organized in a salt-and-pepper pattern. Previous work in the mouse has shown that, in absence of Nanog, all ICM cells adopt a PrE identity. Moreover, the activation or the blockade of the Fgf/RTK pathway biases cell fate specification towards either PrE or Epi, respectively. We show that, in absence of Gata6, all ICM cells adopt an Epi identity. Furthermore, the analysis of Gata6(+/-) embryos reveals a dose-sensitive phenotype, with fewer PrE-specified cells. These results and previous findings have enabled the development of a mathematical model for the dynamics of the regulatory network that controls ICM differentiation into Epi or PrE cells. The model describes the temporal dynamics of Erk signaling and of the concentrations of Nanog, Gata6, secreted Fgf4 and Fgf receptor 2. The model is able to recapitulate most of the cell behaviors observed in different experimental conditions and provides a unifying mechanism for the dynamics of these developmental transitions. The mechanism relies on the co-existence between three stable steady states (tristability), which correspond to ICM, Epi and PrE cells, respectively. Altogether, modeling and experimental results uncover novel features of ICM cell fate specification such as the role of the initial induction of a subset of cells into Epi in the initiation of the salt-and-pepper pattern, or the precocious Epi specification in Gata6(+/-) embryos.