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

Publicated to:CELLULAR AND MOLECULAR LIFE SCIENCES. 81 (1): 246- - 2024-05-31 81(1), DOI: 10.1007/s00018-024-05284-2

Authors: Álvarez-Sánchez A; Grinat J; Doria-Borrell P; Mellado-López M; Pedrera-Alcócer É; Malenchini M; Meseguer S; Hemberger M; Pérez-García V

Affiliations

Centro de Investigación Príncipe Felipe, Calle de Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. - Author
Centro de Investigación Príncipe Felipe, Calle de Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. vperez@cipf.es. - Author
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. - Author
Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge, UK. - Author

Abstract

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.

Keywords

AnimalsBiosynthetic pathwaysCell differentiationCrispr-cas systemsCrispr/cas9 technologyEndoplasmic reticulumEndoplasmic reticulum stressFemaleGlycosylphosphatidylinositolsHumansMicePlacentaPlacental syncytiotrophoblastPlacentationPre-eclampsiaPreeclampsiaPregnancyTrophoblast stem cellsTrophoblastsUnfolded protein responseWnt signaling pathway

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal CELLULAR AND MOLECULAR LIFE SCIENCES due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 46/205, thus managing to position itself as a Q1 (Primer Cuartil), in the category Cell Biology.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-06-24:

  • Scopus: 4

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-24:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 13.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 13 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 26.1.
  • The number of mentions on the social network X (formerly Twitter): 14 (Altmetric).
  • The number of mentions in news outlets: 2 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Canada.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: Last Author (Perez-Garcia V).