Transcriptional control of the endocrine pancreas

The general objectives of this thesis were to describe the role and function of several transcription factors vitally important in the development and maintenance of the pancreas through three lines of research. Firstly, neurogenin3 (ngn3) is vitally important to the development of the islets of Langerhans. Knocking out this gene prevents mice from developing endocrine cells of the pancreas (islets of Langerhans). This thesis set out to label the ngn3 positive precursor cell population in developing mice, and characterise their phenotype. marking cells that are developmentally important to pancreas function, and being able to identify their phenotype, may provide clues to markers that could be exploited as targets for future diabetes therapies. Secondly, pancreatic duodenal homeobox-1 (PDX-1) is another critically important transcription factor in both pancreas development and in maintaining the insulin expression of the β cells in the islets of Langerhans. Preventing PDX-1 function causes severe agenesis of the pancreas, and mutations in the gene cause one form of diabetes. This thesis describes the production of a super-activated form of the PDX-1 protein using the transactivation domain VP16. The use of the PDX-1VP16 protein could provide a potential starting point for research into driving differentiation of stem cells to a pancreatic phenotype. Finally, there are four transcription factors that are known to drive expression of the insulin gene synergistically. They are the homeodomain protein PDX-1, the leucine zipper protein MafA, and the basic helix loop helix heterodimer β2/E47. Understanding how the transcription factors that drive insulin expression interact on the promoter in vivo could be used for future studies to understand the process of insulin gene transcription both in healthy and diabetic patients.EThOS - Electronic Theses Online ServiceGBUnited Kingdo