The multifunctional protein beta-catenin and pancreatic organogenesis

During pancreatic organogenesis, all mature cell types in the pancreas arise from common multipotent pancreatic progenitor cells (MPCs), localized to the distal tip of the expanding epithelium. The dysfunction or destruction of pancreatic β-cells results in diabetes. Endeavors to treat this disease by replacing β-cells with new cells generated from stem cells will benefit from exploiting the pathways involved in the normal development of this pancreatic cell type from MPCs. Prior studies indicated that the protein β-catenin was required for the development of exocrine acinar cells, but the precise role of β-catenin in endocrine cell development remained controversial. β-catenin also performs two separate functions, one as a crucial component of canonical Wnt signaling and the other at cell-cell junctions where it binds with E-cadherin to stabilize adherens junctions. The purpose of this dissertation is to understand and separate the specific roles of β-catenin, whether signaling or structural in nature during pancreas development and β-cell development, particularly as it relates to the growth and maintenance of MPCs. Following the elimination of all β-catenin function in the early pancreas, I found that β-catenin is not required for the differentiation of β-cells, but that it was required to establish β-cell mass. This requirement played out not in β-cells themselves, but at the level of normally specified MPCs, in which β-catenin is necessary to both expand and maintain distal patterning in progenitors, providing a sufficient number of progenitors capable of producing β-cells. To determine whether the observed growth and patterning defects were due to the signaling or structural role of β-catenin, I use a signaling-deficient yet structurally-competent form of the protein. I found that the growth of the pancreas is dependent on the signaling role of β-catenin and surprisingly that patterning and exocrine acinar cell development require the structural role of β-catenin. Thus, both the signaling and structural roles of β-catenin are necessary for separate but equally important aspects of pancreas development. Together, the information presented in this dissertation provides new molecular insights into the role of β-catenin during pancreas and β-cell development.