EGFR signaling promotes β-cell proliferation and survivin expression during pregnancy.

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 pregna...

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Main Authors: Elina Hakonen, Jarkko Ustinov, Jaan Palgi, Päivi J Miettinen, Timo Otonkoski
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2014-01-01
Series:PLoS ONE
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24695557/pdf/?tool=EBI
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spelling doaj-002075132668414f9f07773864b4e7412021-06-19T04:59:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0194e9365110.1371/journal.pone.0093651EGFR signaling promotes β-cell proliferation and survivin expression during pregnancy.Elina HakonenJarkko UstinovJaan PalgiPäivi J MiettinenTimo OtonkoskiPlacental 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24695557/pdf/?tool=EBI
collection DOAJ
language English
format Article
sources DOAJ
author Elina Hakonen
Jarkko Ustinov
Jaan Palgi
Päivi J Miettinen
Timo Otonkoski
spellingShingle Elina Hakonen
Jarkko Ustinov
Jaan Palgi
Päivi J Miettinen
Timo Otonkoski
EGFR signaling promotes β-cell proliferation and survivin expression during pregnancy.
PLoS ONE
author_facet Elina Hakonen
Jarkko Ustinov
Jaan Palgi
Päivi J Miettinen
Timo Otonkoski
author_sort Elina Hakonen
title EGFR signaling promotes β-cell proliferation and survivin expression during pregnancy.
title_short EGFR signaling promotes β-cell proliferation and survivin expression during pregnancy.
title_full EGFR signaling promotes β-cell proliferation and survivin expression during pregnancy.
title_fullStr EGFR signaling promotes β-cell proliferation and survivin expression during pregnancy.
title_full_unstemmed EGFR signaling promotes β-cell proliferation and survivin expression during pregnancy.
title_sort egfr signaling promotes β-cell proliferation and survivin expression during pregnancy.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2014-01-01
description 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.
url https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24695557/pdf/?tool=EBI
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