1715-P: The c-Jun Transcription Factor Regulates Beta-Cell Survival following Prolactin Treatment

Pregnancy and postpartum states drive dynamic expansion and regression of maternal beta-cells in response to changing metabolic demands. We previously identified a critical role for prolactin receptor (PRLR) signaling in orchestrating the gestational expansion of beta-cells. Using single-cell RNA sequencing of mouse islets, we recently identified increased expression of immediate early genes (IEGs) in late gestation and early postpartum beta-cells. Furthermore, expression of a subset of IEGs, including c-Jun, appeared to be mutually exclusive with beta-cells undergoing apoptosis in the postpartum as assessed by TUNEL staining. The c-Jun transcription factor is a well-characterized IEG implicated in regulating proliferation, apoptosis, and survival in various tissues. Therefore, we hypothesized that c-Jun plays a critical role in beta-cell survival within the postpartum islet via PRLR signaling. Using immunostaining we found that c-Jun is normally expressed in islets from late pregnancy and early postpartum but is not present in mice lacking PRLR within beta-cells. This indicated PRLR signaling is required for induction of c-Jun. Prolactin treatment induces c-Jun expression within beta-cells in cultured murine islets as well as islets from a human female donor. Induction of c-Jun by prolactin is mediated by MAPK/ERK but not Stat5 or PI3K signaling as determined by selective inhibition of these pathways. Prolactin has been shown to promote survival of beta-cells. Inhibition of Jun phosphorylation blocks prolactin-mediated protection from dexamethasone-induced apoptosis of beta-cells. Together, these studies suggest c-Jun acts downstream of PRLR / MAPK signaling contributing to the pro-survival effects of prolactin signaling.