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

• DOI: 10.1016/j.celrep.2017.07.035
• Publication Date: 2017-08-08T20:05:54Z
• Authors: Antonio J. Jimene...; Rudolf Pillich; Wendy Yang; Giuseppe R. Diaferia; Paolo Meda; Laura Crisa; Vincenzo Cirulli
• Keywords: Male; 0301 basic medicine; QH301-705.5; Article; sonic hedgehog; Islets of Langerhans; Mice; 03 medical and health sciences; α-catenin; Animals; Cell Lineage; Hedgehog Proteins; Biology (General); Pdx1; Cell Differentiation; SOX9 Transcription Factor; Adherens Junctions; β cells; cell polarity; adherens junctions; Female; pancreas development; islet progenitors; alpha Catenin; Sox9

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.