Insulin is synthesized in beta cells of the islet of Langerhans. Physiological levels of glucose are maintained through the actions of this hormone on peripheral tissues, with defects in beta cell function resulting in hyperglycemia in diabetics. In recent years, substantial evidence has been collected demonstrating that islet-enriched transcriptional regulators of the insulin gene not only play an important role in beta cell function, but also in beta cell formation during development. Our laboratory recently isolated and showed that MafA, a basic leucine-zipper containing transcription factor, is a key activator of insulin gene expression. This factor is first detected in the insulin-producing cells formed during the second and predominant phase of beta cell formation during pancreatic organogenesis, and only in islet beta cells within the pancreas. The developmental expression pattern of MafA is novel, as all other islet-enriched transcription factors are induced earlier and broadly in both non-hormone and hormone-expressing progenitors. Based upon the uniqueness of the MafA expression pattern and the contribution of other closely related Maf proteins in cell differentiation processes, we believe that MafA is involved in defining the expression of genes associated with beta cell identity. Arguably, MafA is a better marker of functional beta cells than even insulin, as hormone expression is also detected in first phase cells that lack glucose-sensing proteins required for normal cell function. To test how significant MafA is to the beta cell, we plan to: (1) determine how MafA influences beta cell activity in vivo; (2) determine how MafA activation is regulated in beta cells; and (3) identify transcriptional targets of MafA in beta cells. These studies will provide greater insight into how fundamental MafA is to the beta cell, and likely provide information that will be valuable in generating acceptable beta-like cells for therapeutic treatment of type 1 and type 2 diabetics.
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