Endocrine Cell Differentiation and Function


Isabella Artner, PI


Diabetes results from loss or dysfunction of insulin producing beta cells in the pancreas. Despite insulin injection treatment, diabetic patients suffer from
long-term complications, such as blindness and kidney failure. Therefore, a central goal of diabetes research is to generate large numbers of functional beta cells for transplantation into diabetic patients. The successful generation of beta cells in vitro will require a thorough understanding of the molecular networks that direct the normal development of these cells. The objective of our research is to understand the molecular and cellular mechanisms that control beta cell maturation and function in the embryonic and adult pancreas. Our research employs genetic engineering in mice as well as biochemical methods.

Maf transcription factors control endocrine cell development and function

To generate functional insulin producing cells for transplantation, the molecular programs initiating beta cell formation, maturation, and insulin production need to be completely understood. Using genetically engineered mouse models, we have examined the role of basic leucine zipper transcription factors MafA and MafB in alpha and beta cell differentiation and function. Maf activators are known regulators of insulin and glucagon transcription in vitro (Matsouka et al., 2003, Artner et al., 2006). Our analysis control the final steps of pancreatic alpha and beta cell differentiation during development (Artner et al., 2007, artner et al., 2010). Mutant animals have fewer insulin and glucagon producing cells, while the number of endocrine precursor cells remains unchanged. A reduction in insulin and glucagon production supports a critical role of MafA and MafB in transcriptional activation of the insulin and glucagon genes. To further assess the function of Maf transcription factors in alpha and beta cell development occupancy (ChIP on chip) techniques to identify novel genes regulating alpha and beta cell differentiation. Candidate genes will be analyzed for their expression and function within the developing and adult pancreas. Functional characterization includes overexpression and knock out experiments (in cell culture, mouse and chick model systems) and chromatin immunoprecipitation assays.

Maf factors and Type 1 Diabetes

Type 1 diabetes is caused by a lack of the insulin hormone. Thus the immune system attacks and destroys all insulin producing beta cells of the pancreas which results in the inhability of patients to control their own blood sugar levels. Recent studies have suggested that this autoimmune attack is caused by a combination of environmental and genetic factors. Viral infection is one of the external triggers implicated in this process. Type 1 interterons protect cells from virus infrections, but too high levels of these proteins cause the development of autoimmune diseases. Proper control of interferon levels is crucial to prevent type 1 diabetes.

Our goal is to understand the role of Maf transcriptional regulators in this process. The Maf transcription factors have been implicated in controlling proper interferon expression as high MafB levels block IFN1B transcription while low MafB expression permits activation of the IFN1B expression.
Human pancreatic β cells express two related Maf proteins, MafA och MafB, but under normal conditions MafB expression is low compared to MafA. We have generated Maf mouse models which allow us to study the effects of high and low MafB expression in β cells in regards to type 1 diabetes development. These Maf mutant mice have many MafB expressing β cells, which is not seen in wild type mice.

Our studies will focus on determining the precise role of Maf transcription factors in type 1 diabetes development.

This knowledge will be essential for understanding the mechanisms of viral-induced diabetes susceptibility and assessing the health status of isolated islets used for transplantation in regards to their vulnerability for viral infections.


Last updated: September 8, 2011
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