The Role of β-Catenin in Pancreatic Progenitors

Diabetes results from diminished function of insulin secreting β-cells, a major cell type of the endocrine pancreas.  Generating functional β-cells de novo offers promise in the treatment of diabetes; however, the cellular mechanisms that drive β-cell development are poorly understood.  Previous studies have shown that the Wnt/β-catenin signaling pathway is necessary for pancreatic development and may be required for maintenance of multipotent progenitor cells (MPC) from which β-cells arise.  We hypothesize that MPCs require Wnt/β-catenin signaling for expansion and maintenance in early development. Our preliminary findings demonstrated that the volume of MPCs in the developing embryonic pancreas remained unaffected when β-catenin levels were diminished at E11.5. However, at E12.5, we noticed a significant reduction in the number of MPCs accompanied by an increase in endocrine cell mass, suggesting that β-catenin is required for maintenance and expansion of MPCs during this period.  To better understand the requirement for β-catenin signaling in MPCs, we will characterize the expression pattern of potential β-catenin target genes by in situ hybridization in β-catenin deficient embryonic pancreata.  We will additionally determine whether the requirement for β-catenin signaling is Wnt dependent by culturing pancreatic explants in the presence of Wnt inhibitors.  These studies will contribute to a better understanding of the requirement for β-catenin signaling in MPCs, potentially elucidating the mechanisms that drive the expansion and maintenance of these progenitors. This knowledge will in turn help us to one day develop a method of generating functional β-cells for therapeutic use.