Multiple Endocrine Neoplasia Type 1 Deletion in Pancreatic α-Cells Leads to Development of Insulinomas in Mice

摘要

The pancreatic α- and β-cells are critical components in regulating blood glucose homeostasis via secretion of glucagon and insulin, respectively. Both cell types are typically localized in the islets of Langerhans. However, little is known about the roles of paracrine interactions that contribute to their physiological functions. The lack of suitable cell lines to study α- and β-cells interactions have led us to develop an α-cell-specific Cre-expressing transgenic line utilizing a glucagon promoter sequence, the Glu-Cre transgenic mouse. Here, we demonstrate that the Glu-Cre could specifically and efficiently excise floxed target genes in adult islet α-cells. We further showed that deletion of the tumor suppressor gene, multiple endocrine neoplasia type 1 (Men1), in α-cells led to tumorigenesis. However, to our surprise, the lack of Men1 in α-cells did not result in glucagonomas but rather β-cell insulinomas. Because deletion of the Men1 alleles was only present in α-cells, our data suggested that cross communication between α- and β-cells contributes to tumorigenesis in the absence of Men1. Together, we believed that the new model systems described here will allow future studies to decipher cellular interactions between islet α- and β-cells in a physiological context.