Maf and Mitf transcription factors regulate pancreatic endocrine cell differentiation and function

Diabetes - the imbalance in glucose homeostasis is partially caused by loss or dysfunction of pancreatic insulin producing β cells or development of insulin resistance. In Type 1 diabetes β cells are destroyed in the process of an autoimmune attack, whereas in Type 2 diabetes, islets produce insufficient amounts of insulin or the insulin cannot be used adequately. So far, the most promising therapy to treat Type 1 diabetes is pancreatic islet transplantation. However, this method cannot be used in a larger scale because of the severe scarcity of donors. Therefore, there is a great and urgent need to develop new methods and therapies. One of the potential sources of obtaining functional insulin cells are human embryonic stem cells (ESC) or inducible pluripotent stem cells (iPS). Hence, differentiating stem cells into functional β-cells requires a detailed understanding of pancreas development with the focus on molecular programs underlying β-cells formation and function. Pancreas development and differentiation of insulin and glucagon secreting cells is a complex process controlled by a variety of transcription factors. Two of these factors, MafA and MafB, have been shown to play a major role in the regulation of several genes critical to pancreas development and endocrine cell formation. MafB is essential for both α- and β-cell differentiation, as mice lacking MafB have fewer insulin+ and glucagon+ cells during pancreas development. In contrast, in mouse embryos lacking MafA, the development of β-cells is normal, but adult animals develop diabetes. In adult animals these two transcription factors have a distinct expression pattern, with MafB being expressed in α-cells, whereas MafA is exclusively found in β-cells. We have performed gene expression profiling of wild type and MafA/B mutant pancreata to identify genes important for β-cell maturation and function. In these microarray studies several known (insulin, glucagon, Glut2, PC2) but also novel genes were shown to be differentially expressed in MafB and ...