Zebrafish endoderm formation is regulated by combinatorial Nodal, FGF and BMP signalling
Zebrafish endoderm formation is regulated by combinatorial Nodal, FGF and BMP signalling
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DOI：
10.1242/dev.02387
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发表时间：
2006-06-01
期刊：
影响因子：
4.6
通讯作者：
Lepage, Thierry
中科院分区：
文献类型：
--
作者：
Poulain, Morgane;Furthauer, Maximilian;Lepage, Thierry
在斑马鱼胚胎中，中胚层和内胚层起源于共同的前体，并在原肠胚形成期间通过很大程度上未知的机制分离。了解调节内胚层和中胚层形成的信号通路如何相互作用，对于了解胚层是如何建立的至关重要。在这里，我们分析了FGF和BMP通路如何与内胚层形成过程中的Nodal信号相互作用。我们发现FGF/ERK通路的激活破坏了胚胎内胚层的形成，并拮抗了活化形式的Tar/Acvr 1b诱导动物极内胚层的能力。相比之下，FGF信号的抑制增加了内胚层前体的数量，并增强了Tar*/Acvr 1b在动物极诱导内胚层的能力。使用FGF受体的药理学抑制剂，我们表明，减少FGF信号部分拯救骨突变胚胎内胚层前体的赤字。此外，我们发现，骨形成蛋白的过度表达妥协内胚层的形成，表明内胚层前体的形成是负调控的骨形成蛋白的腹侧。我们表明，同时抑制FGF/ Ras和BMP途径的结果在内胚层前体的数量急剧增加。总之，这些数据强烈表明BMP和FGF-ERK途径合作，以限制响应Nodal信号传导诱导的内胚层祖细胞的数量。最后，我们研究了FGF-MAPK依赖性抑制内胚层形成的分子基础。我们发现FGF/ERK信号传导导致Casanova/Sox 32（内胚层决定的重要调节因子）磷酸化，并提供证据表明这种磷酸化削弱了其诱导sox 17的能力。这些结果确定了FGF减弱结节诱导的内胚层转录因子的分子机制，并突出了中胚层和内胚层命运可能相互分离的潜在机制。
In the zebrafish embryo, the mesoderm and endoderm originate from common precursors and segregate during gastrulation by mechanisms that are largely unknown. Understanding how the signalling pathways that regulate endoderm and mesoderm formation interact is crucial to understanding how the germ layers are established. Here, we have analysed how the FGF and BMP pathways interact with Nodal signalling during the process of endoderm formation. We found that activation of the FGF/ERK pathway disrupts endoderm formation in the embryo and antagonizes the ability of an activated form of Tar/Acvr1b to induce endoderm at the animal pole. By contrast, inhibition of FGF signalling increases the number of endodermal precursors and potentiates the ability of Tar*/Acvr1b to induce endoderm at the animal pole. Using a pharmacological inhibitor of the FGF receptor, we show that reducing FGF signalling partially rescues the deficit of endoderm precursors in bon mutant embryos. Furthermore, we found that overexpression of BMPs compromises endoderm formation, suggesting that formation of endoderm precursors is negatively regulated by BMPs on the ventral side. We show that simultaneous inhibition of the FGF/ Ras and BMP pathways results in a dramatic increase in the number of endoderm precursors. Taken together, these data strongly suggest that BMP and FGF-ERK pathways cooperate to restrict the number of endodermal progenitors induced in response to Nodal signalling. Finally, we investigated the molecular basis for the FGF-MAPK-dependent repression of endoderm formation. We found that FGF/ERK signalling causes phosphorylation of Casanova/Sox32, an important regulator of endoderm determination, and provide evidence that this phosphorylation attenuates its ability to induce sox17. These results identify a molecular mechanism whereby FGF attenuates Nodal-induced endodermal transcription factors and highlight a potential mechanism whereby mesoderm and endoderm fates could segregate from each other.