α Cell-Specific Men1 Ablation Triggers the Transdifferentiation of Glucagon-Expressing Cells and Insulinoma Development

Abstract

Background & Aims: The tumor suppressor menin is recognized as a key regulator of pancreatic islet development, proliferation, and β-cell function, whereas its role in α cells remains poorly understood. The purpose of the current study was to address this issue in relation to islet tumor histogenesis. Methods: We generated α cell-specific Men1 mutant mice with Cre/loxP technology and carried out analyses of pancreatic lesions developed in the mutant mice during aging. Results: We showed that, despite the α-cell specificity of the GluCre transgene, both glucagonomas and a large amount of insulinomas developed in mutant mice older than 6 months, accompanied by mixed islet tumors. Interestingly, the cells sharing characteristics of both α and β cells were identified shortly after the appearance of menin-deficient α cells but well before the tumor onset. Using a genetic cell lineage tracing analysis, we demonstrated that insulinoma cells were directly derived from transdifferentiating glucagon-expressing cells. Furthermore, our data indicated that the expression of Pdx1, MafA, Pax4, and Ngn3 did not seem to be required for the initiation of this transdifferentiation. Conclusions: Our work shows cell transdifferentiation as a novel mechanism involved in islet tumor development and provides evidence showing that menin regulates the plasticity of differentiated pancreatic α cells in vivo, shedding new light on the mechanisms of islet tumorigenesis. © 2010 AGA Institute.