Pancreatic α-Cell Specific Deletion of Mouse Arx Leads to α-Cell Identity Loss

The specification and differentiation of pancreatic endocrine cell populations (alpha-, beta-, delta, PP-and epsilon-cells) is orchestrated by a combination of transcriptional regulators. In the pancreas, Aristaless-related homeobox gene (Arx) is expressed first in the endocrine progenitors and then restricted to glucagon-producing alpha-cells. While the functional requirement of Arx in early alpha-cell specification has been investigated, its role in maintaining alpha-cell identity has yet to be explored. To study this later role of Arx, we have generated mice in which the Arx gene has been ablated specifically in glucagon-producing alpha-cells. Lineage-tracing studies and immunostaining analysis for endocrine hormones demonstrate that ablation of Arx in neonatal alpha-cells results in an alpha-to-beta-like conversion through an intermediate bihormonal state. Furthermore, these Arx-deficient converted cells express beta-cell markers including Pdx1, MafA, and Glut2. Surprisingly, short-term ablation of Arx in adult mice does not result in a similar alpha-to-beta-like conversion. Taken together, these findings reveal a potential temporal requirement for Arx in maintaining alpha-cell identity.