αE-Catenin Is a Positive Regulator of Pancreatic Islet Cell Lineage Differentiation

The development and function of epithelia depend on the establishment and maintenance of cell-cell adhesion and intercellular junctions, which operate as mechanosensor hubs for the transduction of biochemical signals regulating cell proliferation, differentiation, survival, and regeneration. Here, we show that αE-catenin, a key component of adherens junctions, functions as a positive regulator of pancreatic islet cell lineage differentiation by repressing the sonic hedgehog pathway (SHH). Thus, deletion of αE-catenin in multipotent pancreatic progenitors resulted in (1) loss of adherens junctions, (2) constitutive activation of SHH, (3) decrease in islet cell lineage differentiation, and (4) accumulation of immature Sox9+ progenitors. Pharmacological blockade of SHH signaling in pancreatic organ cultures and in vivo rescued this defect, allowing αE-catenin-null Sox9+ pancreatic progenitors to differentiate into endocrine cells. The results uncover crucial functions of αE-catenin in pancreatic islet development and harbor significant implications for the design of β cell replacement and regeneration therapies in diabetes. [Display omitted] •αE-catenin controls cell-to-cell architectural organization of pancreatic progenitors•Loss of αE-catenin in Pdx1+ cells leads to an increased pool of Sox9+ progenitors•Activation of SHH in αE-cateninnull/Sox9+ cells precludes endocrine specification•Blockade of SHH in αE-cateninnull/Sox9+ cells rescues their endocrine differentiation Jimenez-Caliani et al. examine a regulatory function for αE-catenin in the endocrine differentiation of pancreatic progenitors. Ablation of αE-catenin in multipotent Pdx1+ progenitors disrupts cell-cell adhesion and leads to constitutive activation of SHH signaling that precludes endocrine differentiation and leads to the accumulation of proliferating Sox9+ cells. Pharmacological blockade of SHH rescues the competency of αE-cateninnullSox9+ progenitors to acquire an endocrine phenotype.