Conditional deletion of Men1 in the pancreatic β-cell leads to glucagon-expressing tumor development.

The tumor suppressor menin is recognized as a key regulator of β-cell proliferation. To induce tumorigenesis within the pancreatic β-cells, floxed alleles of Men1 were selectively ablated using Cre-recombinase driven by the insulin promoter. Despite the β-cell specificity of the RipCre, glucagon-expressing tumors as well as insulinomas developed in old mutant mice. These glucagon-expressing tumor cells were menin deficient and expressed the mature α-cell-specific transcription factors Brain-specific homeobox POU domain protein 4 (Brn4) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B (MafB). Moreover, the inactivation of β-cell-specific transcription factors was observed in mutant β-cells. Our work shows that Men1 ablation in the pancreatic β-cells leads to the inactivation of specific transcription factors, resulting in glucagon-expressing tumor development, which sheds light on the mechanisms of islet tumorigenesis.