The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.

The glycosylphosphatidylinositol (GPI) biosynthetic pathway in the endoplasmic reticulum (ER) is crucial for generating GPI-anchored proteins (GPI-APs), which are translocated to the cell surface and play a vital role in cell signaling and adhesion. This study focuses on two integral components of t...

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Autores: Álvarez-Sánchez A, Grinat J, Doria-Borrell P, Mellado-López M, Pedrera-Alcócer É, Malenchini M, Meseguer S, Hemberger M, Pérez-García V
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Centro de Investigación Principe Felipe (CIPF)
Repositorio:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
OAI Identifier:oai:cipf.fundanetsuite.com:p4372
Acceso en línea:https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4372
Access Level:acceso abierto
Palabra clave:CRISPR/Cas9 technology, Endoplasmic reticulum stress, Placental Syncytiotrophoblast, Preeclampsia, Trophoblast stem cells, Unfolded protein response
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spelling The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.Álvarez-Sánchez AGrinat JDoria-Borrell PMellado-López MPedrera-Alcócer ÉMalenchini MMeseguer SHemberger MPérez-García VCRISPR/Cas9 technology, Endoplasmic reticulum stress, Placental Syncytiotrophoblast, Preeclampsia, Trophoblast stem cells, Unfolded protein responseThe glycosylphosphatidylinositol (GPI) biosynthetic pathway in the endoplasmic reticulum (ER) is crucial for generating GPI-anchored proteins (GPI-APs), which are translocated to the cell surface and play a vital role in cell signaling and adhesion. This study focuses on two integral components of the GPI pathway, the PIGL and PIGF proteins, and their significance in trophoblast biology. We show that GPI pathway mutations impact on placental development impairing the differentiation of the syncytiotrophoblast (SynT), and especially the SynT-II layer, which is essential for the establishment of the definitive nutrient exchange area within the placental labyrinth. CRISPR/Cas9 knockout of Pigl and Pigf in mouse trophoblast stem cells (mTSCs) confirms the role of these GPI enzymes in syncytiotrophoblast differentiation. Mechanistically, impaired GPI-AP generation induces an excessive unfolded protein response (UPR) in the ER in mTSCs growing in stem cell conditions, akin to what is observed in human preeclampsia. Upon differentiation, the impairment of the GPI pathway hinders the induction of WNT signaling for early SynT-II development. Remarkably, the transcriptomic profile of Pigl- and Pigf-deficient cells separates human patient placental samples into preeclampsia and control groups, suggesting an involvement of Pigl and Pigf in establishing a preeclamptic gene signature. Our study unveils the pivotal role of GPI biosynthesis in early placentation and uncovers a new preeclampsia gene expression profile associated with mutations in the GPI biosynthesis pathway, providing novel molecular insights into placental development with implications for enhanced patient stratification and timely interventions.BIRKHAUSER VERLAG AG2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4372CMLS-Cellular and Molecular Life SciencesISSN: 1420682XISSNe: 14209071reponame:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)instname:Centro de Investigación Principe Felipe (CIPF)Inglésinfo:eu-repo/semantics/openAccessoai:cipf.fundanetsuite.com:p43722026-06-17T11:19:47Z
dc.title.none.fl_str_mv The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.
title The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.
spellingShingle The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.
Álvarez-Sánchez A
CRISPR/Cas9 technology, Endoplasmic reticulum stress, Placental Syncytiotrophoblast, Preeclampsia, Trophoblast stem cells, Unfolded protein response
title_short The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.
title_full The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.
title_fullStr The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.
title_full_unstemmed The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.
title_sort The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.
dc.creator.none.fl_str_mv Álvarez-Sánchez A
Grinat J
Doria-Borrell P
Mellado-López M
Pedrera-Alcócer É
Malenchini M
Meseguer S
Hemberger M
Pérez-García V
author Álvarez-Sánchez A
author_facet Álvarez-Sánchez A
Grinat J
Doria-Borrell P
Mellado-López M
Pedrera-Alcócer É
Malenchini M
Meseguer S
Hemberger M
Pérez-García V
author_role author
author2 Grinat J
Doria-Borrell P
Mellado-López M
Pedrera-Alcócer É
Malenchini M
Meseguer S
Hemberger M
Pérez-García V
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CRISPR/Cas9 technology, Endoplasmic reticulum stress, Placental Syncytiotrophoblast, Preeclampsia, Trophoblast stem cells, Unfolded protein response
topic CRISPR/Cas9 technology, Endoplasmic reticulum stress, Placental Syncytiotrophoblast, Preeclampsia, Trophoblast stem cells, Unfolded protein response
description The glycosylphosphatidylinositol (GPI) biosynthetic pathway in the endoplasmic reticulum (ER) is crucial for generating GPI-anchored proteins (GPI-APs), which are translocated to the cell surface and play a vital role in cell signaling and adhesion. This study focuses on two integral components of the GPI pathway, the PIGL and PIGF proteins, and their significance in trophoblast biology. We show that GPI pathway mutations impact on placental development impairing the differentiation of the syncytiotrophoblast (SynT), and especially the SynT-II layer, which is essential for the establishment of the definitive nutrient exchange area within the placental labyrinth. CRISPR/Cas9 knockout of Pigl and Pigf in mouse trophoblast stem cells (mTSCs) confirms the role of these GPI enzymes in syncytiotrophoblast differentiation. Mechanistically, impaired GPI-AP generation induces an excessive unfolded protein response (UPR) in the ER in mTSCs growing in stem cell conditions, akin to what is observed in human preeclampsia. Upon differentiation, the impairment of the GPI pathway hinders the induction of WNT signaling for early SynT-II development. Remarkably, the transcriptomic profile of Pigl- and Pigf-deficient cells separates human patient placental samples into preeclampsia and control groups, suggesting an involvement of Pigl and Pigf in establishing a preeclamptic gene signature. Our study unveils the pivotal role of GPI biosynthesis in early placentation and uncovers a new preeclampsia gene expression profile associated with mutations in the GPI biosynthesis pathway, providing novel molecular insights into placental development with implications for enhanced patient stratification and timely interventions.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4372
url https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4372
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BIRKHAUSER VERLAG AG
publisher.none.fl_str_mv BIRKHAUSER VERLAG AG
dc.source.none.fl_str_mv CMLS-Cellular and Molecular Life Sciences
ISSN: 1420682X
ISSNe: 14209071
reponame:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
instname:Centro de Investigación Principe Felipe (CIPF)
instname_str Centro de Investigación Principe Felipe (CIPF)
reponame_str r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
collection r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
repository.name.fl_str_mv
repository.mail.fl_str_mv
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