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

Sci Rep. 2015 Oct 27;5:15672. doi: 10.1038/srep15672.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Dedifferentiation / physiology
  • Cell Lineage
  • Cell Proliferation / physiology
  • Diabetes Mellitus / pathology
  • Gene Expression Regulation / physiology*
  • Green Fluorescent Proteins / genetics
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Hyperglycemia / pathology
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / classification
  • Insulin-Secreting Cells / cytology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / metabolism*
  • Promoter Regions, Genetic / genetics

Substances

  • Homeodomain Proteins
  • Insulin
  • Paired Box Transcription Factors
  • Pax4 protein, mouse
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins