FGF信号通路通过调节小GTPase的活性而调控细胞运动和细胞极性建立

The study of cell motility and establishment of cell polarity is one of the most interesting and attractive issues in biology, however, the mechanisms remain unclear. Our previous study has revealed that FGF signaling influences convergent extension during gastrulation. In this study, we will employ Xenopus laevis as our animal model to systematically address these questions. We will utilize bFGF and SU5402 to turn-on and turn-off FGF signaling respectively, then demonstrate at the embryo, tissue and cell level how FGF signaling regulates convergent extension during Xenopus laevis mesoderm formation. Furthermore, we will use GST pull down, FRET and confocal microscopy to uncover the mechanisms that FGF signaling regulates the activity and localization of small GTPases, which in turn mediates convergent extension. In summary, our study is going to determine how FGF signaling regulates cell motility and cell polarity by regulating the activity and localization of small GTPases. Moreover, our study will shed light on the mechanism of cell motility and the establishment of cell polarity during gastrulation. Finally, this study would help understand the mechanisms of neural tube defect and cancer metastasis which share similar regulatory genes with convergent extension.

关于细胞极性建立的机制问题的探讨一直是生命科学研究中最具吸引力和最热门的领域之一，但很多机制问题至今仍不清楚。我们前期的实验表明FGF信号通路影响原肠胚期胚胎的汇聚伸展，因此，在本项目中，我们选用非洲爪蟾作为模式动物，利用bFGF和FGF抑制剂SU5402分别调控FGF信号通路的开和关，在胚胎水平，组织水平和细胞水平阐明FGF信号通路影响非洲爪蟾胚胎背方中胚层细胞的汇聚伸展；利用GST Pull down、FRET和共聚焦显微技术进一步揭示FGF信号通路通过调节小GTPase的活性而调控胚胎背方中胚层细胞的汇聚伸展的分子机制。本研究结果将首次揭示FGF信号通路通过调节小GTPase的活性与亚细胞定位从而参与协调与控制细胞运动和细胞极性建立的分子机理，加深人们对原肠作用过程中细胞运动和细胞极性建立的理解，而且也为癌细胞转移和神经管发育缺陷的机制研究提供借鉴。

FGF信号通路在脊椎动物胚胎发育，癌症发生及转移等过程中发挥着重要作用。研究FGF信号通路如何调控脊椎动物早期胚胎发育，尤其是FGF信号通路在原肠胚期如何调控细胞命运决定、细胞运动和细胞极性建立等机制问题，将有助于科学认识并干预FGF信号通路，为控制癌细胞转移和神经管发育缺陷等疾病提供理论依据。在本项目中，我们选用热带爪蟾作为模式动物，并利用bFGF和FGF抑制剂SU5402分别“开启”和“关闭”FGF信号通路。我们的研究结果在胚胎水平，组织水平和细胞水平上阐明了FGF信号通路调控爪蟾胚胎细胞运动和细胞命运决定，并进一步揭示了FGF信号通路通过调控Nhes和Nrf2等关键基因而影响细胞运动和细胞分化的分子机制。其中，我们的研究发现Nhes是Notch信号通路的下游基因，而Nrf2已报导，是抗氧化信号通路中的关键转录因子。我们的研究提示，FGF信号通路与Notch和Nrf2/ARE信号通路协同调控细胞命运决定、细胞运动和细胞极性建立。