Prolactin Receptor Signaling Regulates a Pregnancy-Specific Transcriptional Program in Mouse Islets

Endocrinology. 2019 May 1;160(5):1150-1163. doi: 10.1210/en.2018-00991.


Pancreatic β-cells undergo profound hyperplasia during pregnancy to maintain maternal euglycemia. Failure to reprogram β-cells into a more replicative state has been found to underlie susceptibility to gestational diabetes mellitus (GDM). We recently identified a requirement for prolactin receptor (PRLR) signaling in the metabolic adaptations to pregnancy, where β-cell-specific PRLR knockout (βPRLRKO) mice exhibit a metabolic phenotype consistent with GDM. However, the underlying transcriptional program that is responsible for the PRLR-dependent metabolic adaptations during gestation remains incompletely understood. To identify PRLR signaling gene regulatory networks and target genes within β-cells during pregnancy, we performed a transcriptomic analysis of pancreatic islets isolated from either βPRLRKO mice or littermate controls in late gestation. Gene set enrichment analysis identified forkhead box protein M1 and polycomb repressor complex 2 subunits, Suz12 and enhancer of zeste homolog 2 (Ezh2), as novel candidate regulators of PRLR-dependent β-cell adaptation. Gene ontology term pathway enrichment revealed both established and novel PRLR signaling target genes that together promote a state of increased cellular metabolism and/or proliferation. In contrast to the requirement for β-cell PRLR signaling in maintaining euglycemia during pregnancy, PRLR target genes were not induced following high-fat diet feeding. Collectively, the current study expands our understanding of which transcriptional regulators and networks mediate gene expression required for islet adaptation during pregnancy. The current work also supports the presence of pregnancy-specific adaptive mechanisms distinct from those activated by nutritional stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Diabetes, Gestational / genetics
  • Diabetes, Gestational / metabolism
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Gene Ontology
  • Gene Regulatory Networks
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism
  • Pregnancy
  • Receptors, Prolactin / genetics*
  • Receptors, Prolactin / metabolism
  • Signal Transduction / genetics*


  • Receptors, Prolactin
  • Suz12 protein, mouse
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2