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

Abstract

AbstractPancreatic 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 mice lacking β-cell PRLR (βPRLRKO) 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 (Foxm1) and polycomb repressor complex 2 (PRC2) subunits, Suz12 and Ezh2, as novel candidate regulators of PRLR-dependent β-cell adaptation. GO-term pathway enrichment revealed both established and novel PRLR signaling target genes that together describe 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. Altogether, 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.