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

著名遗传学家西奥多西乌斯·多布赞斯基在谈到对生物机制的理解时引用了一句名言：“生物学中没有任何东西是有意义的；除非从进化论的角度来看。”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力，以了解一种名为Wnt信号的突出生物机制的功能，该机制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，它可能导致人类疾病，如癌症和糖尿病。Wnt信号是一种分子途径，调节特定基因在胚胎构建期间以及在一些成人身体器官的维护和再生期间何时何地被开启，但不幸的是，在人类疾病中也是如此。在Wnt途径的末端是一种叫做Tcf的分子。Tcf接触并控制受Wnt信号调控的基因中的DNA序列；当Wnt信号激活时，Tcf启动这些基因，当Wnt信号处于静默状态时，Tcf将它们关闭。在没有脊椎的动物(无脊椎动物)中，只有一种TCF，因此Wnt-TCF途径相对简单。在人类和与脊椎动物(脊椎动物)关系密切的动物中，有许多TCFs。在这里，我们将研究拥有几个不同的TCFs是否使Wnt信号能够执行更多不同的角色，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，也很有可能提高我们对它们在各种疾病(如癌症和糖尿病)中如何做不同事情的理解。在这个项目中，我们将结合几种脊椎动物和密切相关的无脊椎动物关于制造这些不同TCFs的单独基因的信息。我们将研究和剖析不同的脊椎动物TCFs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)中的重要作用，许多生物医学研究人员对Wnt通路在正常生物学和这些疾病中的作用感兴趣，特别是TCF分子的作用。然而，采用强大的比较方法，就像我们在这个项目中所做的那样，还没有尝试过。我们的方法将为我们提供独特的新见解，了解正常胚胎形成的这一重要生物医学机制，最终也是人类疾病。

"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.