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

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.

Keywords: Men1 Ablation, Pancreatic α Cells, Transdifferentiation, Insulinoma

Abbreviations used in this paper: β-gal, β-galactosidase, KO, knockout, MEN1, multiple endocrine neoplasia type 1, Ngn3, neuroginin 3, PCR, polymerase chain reaction