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

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