c-Jun regulates postpartum β-cell apoptosis and survival downstream of prolactin signaling

Pregnancy and postpartum states drive dynamic expansion and regression of maternal β-cell mass. Little is known about what regulates postpartum regression. We recently profiled murine islets from late gestation and early postpartum to identify regulators of β-cell apoptosis or survival. One hit was c-Jun, a transcription factor which regulates proliferation, apoptosis, and survival in various tissues. Here, we examine c-Jun regulation and function during gestation and postpartum and in murine and human islets. To examine the regulation of c-Jun within β-cells we used a mouse genetic model lacking β-cell prolactin receptor (PRLR) and stimulation of human and murine cultured islets with recombinant prolactin. Knockdown of c-Jun in MIN6 cells was accomplished using siRNA and lentiviral-shRNA, or in islets using pharmacologic inhibitors. We found that c-Jun expression in β-cells is temporally restricted to late gestation and early postpartum and requires PRLR signaling. Moreover, c-Jun expression was mutually exclusive with apoptotic β-cells identified by TUNEL staining. Prolactin treatment induces c-Jun expression downstream of MAPK/ERK signaling in both murine and human islets. Inhibition of c-Jun blocks prolactin-mediated survival of β-cells following pro-apoptotic stress, via the pro-survival factors Bcl2l1 (Bcl-xL) and Birc5 (Survivin). Finally, islets from pregnant donors exhibit increased c-Jun expression in β-cells, while absent in β-cells from donors with gestational diabetes (GDM). Together, our findings indicate that c-Jun contributes to pro-survival effects of lactogens downstream of PRLR/MAPK signaling in β-cells. c-Jun regulation is conserved in human islets and pregnancy and dysregulated in GDM.