Abstract
Placental lactogen (PL) induced serotonergic signaling is essential for gestational β-cell mass expansion. We have previously shown that intact Epidermal growth factor –receptor (EGFR) function is a crucial component of this pathway. We now explored more specifically the link between EGFR and pregnancy-induced β-cell mass compensation. Islets were isolated from wild-type and β-cell-specific EGFR-dominant negative mice (E1-DN), stimulated with PL and analyzed for β-cell proliferation and expression of genes involved in gestational β-cell growth. β-cell mass dynamics were analyzed both with traditional morphometrical methods and three-dimensional optical projection tomography (OPT) of whole-mount insulin-stained pancreata. Insulin-positive volume analyzed with OPT increased 1.4-fold at gestational day 18.5 (GD18.5) when compared to non-pregnant mice. Number of islets peaked by GD13.5 (680 vs 1134 islets per pancreas, non-pregnant vs. GD13.5). PL stimulated beta cell proliferation in the wild-type islets, whereas the proliferative response was absent in the E1-DN mouse islets. Serotonin synthesizing enzymes were upregulated similarly in both the wild-type and E1-DN mice. However, while survivin (Birc5) mRNA was upregulated 5.5-fold during pregnancy in the wild-type islets, no change was seen in the E1-DN pregnant islets. PL induced survivin expression also in isolated islets and this was blocked by EGFR inhibitor gefitinib, mTOR inhibitor rapamycin and MEK inhibitor PD0325901. Our 3D-volumetric analysis of β-cell mass expansion during murine pregnancy revealed that islet number increases during pregnancy. In addition, our results suggest that EGFR signaling is required for lactogen-induced survivin expression via MAPK and mTOR pathways.
Highlights
Pregnancy is one of the most robust physiological stimuli of bcell mass expansion in the adult pancreas
The most important factors leading to b-cell mass expansion during pregnancy are the lactogenic hormones prolactin (Prl) and placental lactogen (PL) which both activate the prolactin receptor (Prl-R) [3]
Epidermal growth factor –receptor (EGFR) signaling has been linked to both b-cell replication and differentiation [23,24,25,26]
Summary
Pregnancy is one of the most robust physiological stimuli of bcell mass expansion in the adult pancreas. This compensates for the rise in insulin demand, which is due to reduced insulin sensitivity in target tissues. The most important factors leading to b-cell mass expansion during pregnancy are the lactogenic hormones prolactin (Prl) and placental lactogen (PL) which both activate the prolactin receptor (Prl-R) [3]. Ligand-binding to the Prl-R leads to activation of the janus kinase 2 (JAK2)-signal transducer and STAT5 pathways [4]. Placental lactogen controls b-cell mass expansion at multiple levels, including upregulation of serotonin synthesis by b-cells [7,9], induction of the transcription factor FoxM1 [10], downregulation of Menin [11], and upregulation of survivin (Birc5) [6]
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