Shifley Emily T, Kenny Alan P, Rankin Scott A, Zorn Aaron M
Perinatal Institute, Divisions of Developmental Biology, University of Cincinnati, Cincinnati, OH 45229, USA.
BMC Dev Biol. 2012 Sep 18;12:27. doi: 10.1186/1471-213X-12-27.
FGF signaling plays numerous roles during organogenesis of the embryonic gut tube. Mouse explant studies suggest that different thresholds of FGF signaling from the cardiogenic mesoderm induce lung, liver, and pancreas lineages from the ventral foregut progenitor cells. The mechanisms that regulate FGF dose in vivo are unknown. Here we use Xenopus embryos to examine the hypothesis that a prolonged duration of FGF signaling from the mesoderm is required to induce foregut organs.
We show that both mesoderm and FGF signaling are required for liver and lung development in Xenopus; formally demonstrating that this important step in organ induction is conserved with other vertebrate species. Prolonged contact with the mesoderm and persistent FGF signaling through both MEK and PI3K over an extended period of time are required for liver and lung specification. Inhibition of FGF signaling results in reduced liver and lung development, with a modest expansion of the pancreas/duodenum progenitor domain. Hyper-activation of FGF signaling has the opposite effect expanding liver and lung gene expression and repressing pancreatic markers. We show that FGF signaling is cell autonomously required in the endoderm and that a dominant negative FGF receptor decreases the ability of ventral foregut progenitor cells to contribute to the lung and liver buds.
These results suggest that the liver and lungs are specified at progressively later times in development requiring mesoderm contact for different lengths of time. Our data suggest that this is achieved at least in part through prolonged FGF signaling. In addition to providing a foundation for further mechanistic studies on foregut organogenesis using the experimental advantages of the Xenopus system, these data have implications for the directed differentiation of stem cells into foregut lineages.
成纤维细胞生长因子（FGF）信号在胚胎肠管的器官发生过程中发挥着多种作用。小鼠外植体研究表明，来自心源性中胚层的不同FGF信号阈值可诱导腹侧前肠祖细胞分化为肺、肝和胰腺谱系。体内调节FGF剂量的机制尚不清楚。在此，我们利用非洲爪蟾胚胎来检验以下假设：中胚层持续的FGF信号是诱导前肠器官所必需的。
我们发现，中胚层和FGF信号对于非洲爪蟾的肝脏和肺发育都是必需的；正式证明了器官诱导中的这一重要步骤在其他脊椎动物物种中是保守的。肝脏和肺的特化需要与中胚层长时间接触，并通过MEK和PI3K持续进行长时间的FGF信号传导。抑制FGF信号会导致肝脏和肺发育减少，胰腺/十二指肠祖细胞区域适度扩张。FGF信号的过度激活则产生相反的效果，扩大肝脏和肺的基因表达并抑制胰腺标志物。我们表明，FGF信号在内胚层中是细胞自主所需的，并且显性负性FGF受体会降低腹侧前肠祖细胞对肺和肝芽的贡献能力。
这些结果表明，肝脏和肺在发育过程中逐渐在较晚的时间被特化，需要与中胚层接触不同的时间长度。我们的数据表明，这至少部分是通过延长FGF信号来实现的。除了为利用非洲爪蟾系统的实验优势对前肠器官发生进行进一步的机制研究提供基础外，这些数据对将干细胞定向分化为前肠谱系也有启示意义。
