Neuregulin-1-mediated ErbB2–ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation

Neuregulin-1-mediated ErbB2–ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation

During placentation, foetal trophoblasts invade deeply into maternal tissue to establish a foeto–maternal circulation. We have previously shown that extravillous trophoblast (EVT) lineage cells express ErbB2 and ErbB3, of which the potential as an oncogenic unit is well established. However, a physi...

Full description

Bibliographic Details
Main Authors: Fock, Valerie, Plessl, Kerstin, Draxler, Peter, Otti, Gerlinde Regina, Fiala, Christian, Knöfler, Martin, Pollheimer, Jürgen
Format: Online
Language:English
Published: The Company of Biologists 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712818/
id pubmed-4712818
recordtype oai_dc
spelling pubmed-47128182016-02-05 Neuregulin-1-mediated ErbB2–ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation Fock, Valerie Plessl, Kerstin Draxler, Peter Otti, Gerlinde Regina Fiala, Christian Knöfler, Martin Pollheimer, Jürgen Research Article During placentation, foetal trophoblasts invade deeply into maternal tissue to establish a foeto–maternal circulation. We have previously shown that extravillous trophoblast (EVT) lineage cells express ErbB2 and ErbB3, of which the potential as an oncogenic unit is well established. However, a physiological function of this receptor combination in humans remains a puzzling question. Here, we demonstrate neuregulin 1 (NRG1) expression and secretion by human decidual stromal cells. Stimulation of human primary trophoblasts with exogenous NRG1 induced phosphorylation of ErbB2, ErbB3 and related downstream effectors. Co-immunoprecipitation experiments confirmed the formation of ErbB2–ErbB3 dimers upon ligand engagement. Along this line, receptor knockdown and ErbB3 neutralization strongly diminished NRG1-dependent activation of the signalling complex. Functional studies revealed that NRG1 promotes EVT formation in placental explant cultures. Although, in the presence of NRG1, basal and camptothecin-induced trophoblast apoptosis was significantly repressed, this effect was abolished upon ErbB3 inhibition. Notably, camptothecin provoked a strong reduction of trophoblast cell column size, whereas NRG1-treated explants were refractory to the compound. Taken together, our findings newly identify a physiological function of the NRG1–ErbB2–ErbB3 axis in trophoblast survival during human placental development. The Company of Biologists 2015-12-01 /pmc/articles/PMC4712818/ /pubmed/26490994 http://dx.doi.org/10.1242/jcs.176933 Text en © 2015. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Fock, Valerie
Plessl, Kerstin
Draxler, Peter
Otti, Gerlinde Regina
Fiala, Christian
Knöfler, Martin
Pollheimer, Jürgen
spellingShingle Fock, Valerie
Plessl, Kerstin
Draxler, Peter
Otti, Gerlinde Regina
Fiala, Christian
Knöfler, Martin
Pollheimer, Jürgen
Neuregulin-1-mediated ErbB2–ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation
author_facet Fock, Valerie
Plessl, Kerstin
Draxler, Peter
Otti, Gerlinde Regina
Fiala, Christian
Knöfler, Martin
Pollheimer, Jürgen
author_sort Fock, Valerie
title Neuregulin-1-mediated ErbB2–ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation
title_short Neuregulin-1-mediated ErbB2–ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation
title_full Neuregulin-1-mediated ErbB2–ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation
title_fullStr Neuregulin-1-mediated ErbB2–ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation
title_full_unstemmed Neuregulin-1-mediated ErbB2–ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation
title_sort neuregulin-1-mediated erbb2–erbb3 signalling protects human trophoblasts against apoptosis to preserve differentiation
description During placentation, foetal trophoblasts invade deeply into maternal tissue to establish a foeto–maternal circulation. We have previously shown that extravillous trophoblast (EVT) lineage cells express ErbB2 and ErbB3, of which the potential as an oncogenic unit is well established. However, a physiological function of this receptor combination in humans remains a puzzling question. Here, we demonstrate neuregulin 1 (NRG1) expression and secretion by human decidual stromal cells. Stimulation of human primary trophoblasts with exogenous NRG1 induced phosphorylation of ErbB2, ErbB3 and related downstream effectors. Co-immunoprecipitation experiments confirmed the formation of ErbB2–ErbB3 dimers upon ligand engagement. Along this line, receptor knockdown and ErbB3 neutralization strongly diminished NRG1-dependent activation of the signalling complex. Functional studies revealed that NRG1 promotes EVT formation in placental explant cultures. Although, in the presence of NRG1, basal and camptothecin-induced trophoblast apoptosis was significantly repressed, this effect was abolished upon ErbB3 inhibition. Notably, camptothecin provoked a strong reduction of trophoblast cell column size, whereas NRG1-treated explants were refractory to the compound. Taken together, our findings newly identify a physiological function of the NRG1–ErbB2–ErbB3 axis in trophoblast survival during human placental development.
publisher The Company of Biologists
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712818/
_version_ 1613524028213952512

Similar Items