PAX4 Defines an Expandable β-Cell Subpopulation in the Adult Pancreatic Islet

Abstract

PAX4 is a key regulator of pancreatic islet development whilst in adult acute overexpression protects β-cells against stress-induced apoptosis and stimulates proliferation. Nonetheless, sustained PAX4 expression promotes β-cell dedifferentiation and hyperglycemia, mimicking β-cell failure in diabetic patients. Herein, we study mechanisms that allow stringent PAX4 regulation endowing favorable β-cell adaptation in response to changing environment without loss of identity. To this end, PAX4 expression was monitored using a mouse bearing the enhanced green fluorescent protein (GFP) and cre recombinase construct under the control of the islet specific pax4 promoter. GFP was detected in 30% of islet cells predominantly composed of PAX4-enriched β-cells that responded to glucose-induced insulin secretion. Lineage tracing demonstrated that all islet cells were derived from PAX4+ progenitor cells but that GFP expression was confined to a subpopulation at birth which declined with age correlating with reduced replication. However, this GFP+ subpopulation expanded during pregnancy, a state of active β-cell replication. Accordingly, enhanced proliferation was exclusively detected in GFP+ cells consistent with cell cycle genes being stimulated in PAX4-overexpressing islets. Under stress conditions, GFP+ cells were more resistant to apoptosis than their GFP- counterparts. Our data suggest PAX4 defines an expandable β-cell sub population within adult islets.

The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences

“…During pancreas development PAX4 is initially expressed in all endocrine progenitors [20,21], being thereafter implicated in the commitment of β/δ progenitors and further development of β-cells [22,23]. The lack of this gene in mouse models leads to the near absence of β- and δ-cells, coupled to an increase in the number of α-cells, rendering the animals severely hyperglycemic leading to neonatal death [22,23,24].…”

“…A recent report from our group has shown that, in adult mouse islets, PAX4 expression is only detected in a subpopulation of β-cells that are prone to proliferation and more resistant to apoptosis. Furthermore, the relative abundance of this subpopulation of PAX4 + β-cells correlates with the proliferative capacity of the islets [21], leading us to speculate that this subpopulation of PAX4 + β-cells is responsible for β-cell plasticity in response to external stimuli in vivo.…”

“…The existence in adult islets of a subpopulation of insulin-expressing β-cells that specifically express PAX4 [21], suggests that PAX4 expression above a specific threshold is required for inhibition of these mature β-cell markers. In support of this hypothesis, only after long term ectopic expression of PAX4 in β-cells in vivo emerges a proliferative PDX1 + /insulin − cell population, indicative of the dedifferentiation of the β-cells [37].…”

“…Further analysis or these microarray data revealed a functional enrichment in cell cycle pathway after PAX4 overexpression. In silico analysis of this pathway indicated that overexpression of PAX4 increases the expression of both cell cycle activators and cell cycle inhibitors, suggesting that PAX4 defines a proliferation permissive β-cell subpopulation primed to expansion only under conditions that alleviate cell cycle breaks [21]. …”

“…The relative abundance of this subpopulation of PAX4 + β-cells increases under physiological situations that require an increase in the proliferation of β-cells such as pregnancy [21] indicating a stringent regulation of this factor even within a single cell phenotype.…”