The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development.
Por:
Álvarez-Sánchez A, Grinat J, Doria-Borrell P, Mellado-López M, Pedrera-Alcócer É, Malenchini M, Meseguer S, Hemberger M and Pérez-García V
Publicada:
31 may 2024
Resumen:
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.
Filiaciones:
Álvarez-Sánchez A:
Centro de Investigación Príncipe Felipe, Calle de Eduardo Primo Yúfera, 3, 46012, Valencia, Spain
Grinat J:
Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge, UK
Doria-Borrell P:
Centro de Investigación Príncipe Felipe, Calle de Eduardo Primo Yúfera, 3, 46012, Valencia, Spain
Mellado-López M:
Centro de Investigación Príncipe Felipe, Calle de Eduardo Primo Yúfera, 3, 46012, Valencia, Spain
Pedrera-Alcócer É:
Centro de Investigación Príncipe Felipe, Calle de Eduardo Primo Yúfera, 3, 46012, Valencia, Spain
Malenchini M:
Centro de Investigación Príncipe Felipe, Calle de Eduardo Primo Yúfera, 3, 46012, Valencia, Spain
Meseguer S:
Centro de Investigación Príncipe Felipe, Calle de Eduardo Primo Yúfera, 3, 46012, Valencia, Spain
Hemberger M:
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada
:
Centro de Investigación Príncipe Felipe, Calle de Eduardo Primo Yúfera, 3, 46012, Valencia, Spain.
Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
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