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

ReferenceBB/S016856/1
Principal Investigator / Supervisor Dr David Ferrier
Co-Investigators /
Co-Supervisors
Institution University of St Andrews
DepartmentBiology
Funding typeResearch
Value (£) 418,478
StatusCompleted
TypeResearch Grant
Start date 01/01/2020
End date 31/12/2022
Duration36 months

Abstract

We aim to provide insight into the origins and molecular bases for the diversity of TCF functions downstream of Wnt signalling in vertebrate development. Wnt/beta catenin/TCF signalling mediates diverse roles in embryonic development, stem-cell-mediated regeneration and human disease. While the upstream Wnt/beta-catenin pathway is remarkably conserved; the diversity of functions in vertebrates clearly correlates with increased diversity of TCF transcription factors expressed from vertebrate genomes. In this interdisciplinary collaboration we will investigate how this step change in TCF diversity contributes to diversification of Wnt function in vertebrates. We will test the hypothesis that whole-genome duplications led to diversification of vertebrate TCF genes and possibly increased isoform-coding, which then enabled acquisition of redundancy, as well as, segregated (sub-functionalisation) and novel functions (neo-functionalisation) in vertebrates. We will particularly investigate whether the vertebrate TCF7E isoform retains functions of the invertebrate TCF and explore whether the TCF diversity is particularly important for embryonic development of the vertebrate CNS. We will meticulously compare gene structure and synteny of TCF genes in genomes of different vertebrates with those of the most closely related invertebrates, the chordates Ciona and amphioxus. We will determine the embryonic expression of TCF genes and isoforms, and assay their function in the Xenopus vertebrate model and in the chordate invertebrate Ciona. We will be able to carry out exciting cross-species TCF swap experiments to assess the extent to which ancestral functions are retained in vertebrate TCF orthologs and in vertebrate embryos. This project will produce a comprehensive understanding of the origin of the diversity of vertebrate TCF structure and the functional impacts in vertebrates, with far-reaching implications for the understanding of Wnt signalling in human disease biology.

Summary

"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.

Impact Summary

This project represents fundamental research with immediate academic impact and potential for future impact on biotechnology and health services. ACADEMIC IMPACT: This will be achieved through open access publications in high-impact, peer-reviewed international journals. Impact will also be promoted by attendance by the applicants and supported post-doctoral researchers at international conferences to present the project results. Meetings targeted will include international Wnt conferences and developmental biology conferences such as those of the British, American and International Societies of Developmental Biology and the European and Pan-American Evolutionary Developmental Biology Societies. Academic beneficiaries will primarily be developmental biologists, particularly those working on Wnt signalling function and mechanisms and those interested in the evolution of developmental processes. Additional academic beneficiaries that are reached, particularly through the Wnt meetings, will include biomedical, cancer and diabetes researchers. The post-doctoral researchers on this project will also directly benefit from career development and skills training in an interdisciplinary and collaborative research environment. PUBLIC UNDERSTANDING OF SCIENCE IMPACT: The general public are also interested in both the evolution of biological diversity on this planet and the causes of human disease. Impact on the general public will be pursued through press releases from our University press offices. We will also expand the Tcf/Lef family Wikipedia web-page, since this is often the first port-of-call for most people when trying to find out about a topic. This Wikipedia page is currently very sparse. We will also contribute to public outreach and widening access events, including Science Week (e.g. with a display of amphioxus and Ciona adults alongside Xenopus tadpoles), with posters and scientists on hand to discuss use of these animals in a comparative fashion to help understand human biology and disease. School visits to our Universities (e.g. via the First Chances widening access program at St Andrews) are another avenue for us to introduce our study species to school children and explain the concept of model systems to study medically relevant biology. We will also run a student summer internship program (USTAN). We will also extend David Ferrier's existing link to the St Andrews public aquarium (60,000 visitors per year), producing a display of Ciona and Xenopus alongside a poster explaining their usefulness in studying fundamental biology relevant to human development and disease. A similar exhibit will also be produced in the new public outreach space in the redeveloped Gatty Laboratory, which faces onto the Fife coastal path and East Sands beach, with over 55,000 users of the coastal path alone each year. IMPACT ON FUTURE RESEARCH: This research project will have direct impact on the two collaborating research groups and their Universities. This project provides the strong foundation for addressing further research questions with future investigations of specific functions of vertebrate TCF genes and of the regulatory mechanisms controlling alternative isoform expression, such as tissue-specific alternative splicing regulators. We are also keen to expand our analysis of TCF isoform expression and function to cancer genomes and gene expression data from cancer biopsy samples. IMPACT ON BIOTECHNOLOGY: Our connection with Nanopore will improve application of their technology for studying alternative mRNA expression. As a follow-up to this project, we plan the development of isoform-specific antibody tools with biotech companies. Such isoform-specific antibody tools could become useful for diagnosis of specific subtypes of colorectal cancer.
Committee Research Committee C (Genes, development and STEM approaches to biology)
Research TopicsStructural Biology
Research PriorityX – Research Priority information not available
Research Initiative X - not in an Initiative
Funding SchemeX – not Funded via a specific Funding Scheme
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