DIVERSIFICATION OF VERTEBRATE T-CELL FACTOR (TCF) STRUCTURE AND FUNCTION IN EVOLUTION AND DEVELOPMENT

“生物学上没有任何东西是有意义的；这是著名遗传学家狄奥多西·多布赞斯基关于理解生物机制的名言。在这里，我们建议遵循他的建议，以获得独特的，新颖的和基本的洞察一个突出的生物学机制的功能，称为Wnt信号，通常调节人类和其他动物的胚胎形成和再生。我们还知道，当Wnt信号有缺陷或异常激活时，它可能导致癌症和糖尿病等人类疾病。Wnt信号是一种分子通路，在胚胎形成过程中，以及在一些成人器官的维持和再生过程中，调节特定基因的开启地点和时间，但不幸的是，在人类疾病中也是如此。在Wnt通路的末端是一种叫做TCF的分子。TCF接触并控制由Wnt信号调节的基因中的“开关”DNA序列；当Wnt信号活跃时，TCF打开这些基因，当Wnt信号沉默时，TCF关闭它们。在没有脊椎骨的动物（无脊椎动物）中，只有一个TCF，因此Wnt-TCF通路相对简单。在人类和与脊骨密切相关的动物（脊椎动物）中，有许多tcf。在这里，我们将研究几种不同的tcf是否能够使Wnt信号发挥更多样化的作用，以帮助构建更复杂的脊椎动物和人类的身体。了解不同的TCF蛋白如何对它们在胚胎中控制的基因产生不同的影响，也极有可能提高我们对它们如何在各种疾病（如癌症和糖尿病）中发挥不同作用的理解。在这个项目中，我们将结合来自几种脊椎动物和密切相关的无脊椎动物的信息，研究产生这些不同tcf的不同基因。我们将研究和剖析不同的脊椎动物tcf的不同和独特的作用。由于Wnt信号在人类疾病（如肠癌、肝癌和2型糖尿病）中的突出作用，许多生物医学研究人员有兴趣研究Wnt通路在正常生物学和这些疾病中的作用，特别是TCF分子的作用。然而，像我们在这个项目中将要做的那样，还没有尝试过采用强有力的比较方法。我们的方法将为我们提供独特的新见解，以了解正常胚胎形成的重要生物医学机制，最终也包括人类疾病。

"Nothing in biology makes any sense; except in the light of evolution" is the famous quote by the eminent geneticist Theodosius Dobzhansky about the understanding of biological mechanisms. Here we propose to follow his advice in order to gain unique, novel and fundamental insight into the function of a prominent biological mechanism, called Wnt signalling, which normally regulates embryo formation and regeneration in humans and other animals. We also know that Wnt signalling can contribute to human disease, such as cancer and diabetes, when it is defective or is abnormally activated.Wnt signalling is a molecular pathway that regulates where and when specific genes are switched on during the building of the embryo, and during maintenance and regeneration of some adult body organs, but unfortunately also in human disease. At the end of the Wnt pathway is a molecule called TCF. TCF contacts and controls the 'switch' DNA sequences in genes that are regulated by Wnt signalling; TCF switches these genes on, when Wnt signalling is active and switches them off, where Wnt signalling is silent. In animals without a backbone (invertebrates) there is just one TCF, so that the Wnt-TCF pathway is relatively straightforward. In humans and closely related animals with backbones (vertebrates) there are many TCFs. Here we will investigate whether having several different TCFs enables Wnt signalling to carry out much more diverse roles to help build the bodies of more complex vertebrates and humans. Knowing how the different TCF proteins have different effects on the genes that they control in the embryo is also highly likely to improve our understanding of how they do different things in various diseases, like cancer and diabetes.In this project we will combine information from several vertebrates and closely related invertebrates on the separate genes that make these different TCFs. We will examine and dissect the different and unique roles of the distinct vertebrate TCFs. Because of the prominent role of Wnt signalling in human disease, such as bowel and liver cancer and Type-2 diabetes, many biomedical researchers are interested in studying the role of the Wnt pathway in normal biology and in these diseases, including specifically the role of TCF molecules. However, adopting the powerful comparative approach, as we will do in this project, has not yet been tried. Our approach will provide us with unique novel insights into this important biomedical mechanism for normal embryo formation, and ultimately also human disease.