| First Author | Hakonen E | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 4 | Pages | e93651 |
| PubMed ID | 24695557 | Mgi Jnum | J:215030 |
| Mgi Id | MGI:5604560 | Doi | 10.1371/journal.pone.0093651 |
| Citation | Hakonen E, et al. (2014) EGFR signaling promotes beta-cell proliferation and survivin expression during pregnancy. PLoS One 9(4):e93651 |
| abstractText | Placental lactogen (PL) induced serotonergic signaling is essential for gestational beta-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 beta-cell mass compensation. Islets were isolated from wild-type and beta-cell-specific EGFR-dominant negative mice (E1-DN), stimulated with PL and analyzed for beta-cell proliferation and expression of genes involved in gestational beta-cell growth. beta-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 beta-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. |
