Distinct requirements for beta-catenin in pancreatic epithelial growth and patterning

Pancreatic exocrine and endocrine lineages arise from multipotent pancreatic progenitor cells (MPCs). Exploiting the mechanisms that govern expansion and differentiation of these cells could enhance efforts to generate beta-cells from stem cells. Although our prior work indicates that the canonical Wnt signaling component beta-catenin is required qualitatively for exocrine acinar but not endocrine development, precisely how this requirement plays out at the level of MPCs and their lineage-restricted progeny is unknown. In addition, the contribution of beta-catenin function to beta-cell development remains controversial. To resolve the potential roles of beta-catenin in development of MPCs and beta-cells, we generated pancreas- and pre-endocrine-specific beta-catenin knockout mice. Pancreas-specific loss of beta-catenin produced not only a dramatic reduction in acinar cell numbers, but also a significant reduction in beta-cell mass. The loss of beta-cells is due not to a defect in the differentiation of endocrine precursors, but instead correlates with an early and specific loss of MPCs. In turn, this reflects a novel role for beta-catenin in maintaining proximal-distal patterning of the early epithelium, such that distal MPCs resort to a proximal, endocrine-competent trunk fate when beta-catenin is deleted. Moreover, beta-catenin maintains proximal-distal patterning, in part, by inhibiting Notch signaling. Subsequently, beta-catenin is required for proliferation of both distal and proximal cells, driving overall organ growth. In distinguishing two distinct roles for beta-catenin along the route of beta-cell development, we suggest that temporally appropriate positive and negative manipulation of this molecule could enhance expansion and differentiation of stem cell-derived MPCs. (C) 2014 Elsevier Inc. All rights reserved.