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

• Main Authors: Antonio J. Jimenez-Caliani, Rudolf Pillich, Wendy Yang, Giuseppe R. Diaferia, Paolo Meda, Laura Crisa, Vincenzo Cirulli
• Format: Article
• Language: English
• Published: Elsevier 2017-08-01
• Series: Cell Reports
• Subjects: pancreas development; islet progenitors; β cells; α-catenin; cell polarity; adherens junctions; Sox9; Pdx1; sonic hedgehog
• Online Access: http://www.sciencedirect.com/science/article/pii/S221112471731001X

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.