Alvarez-Sanchez 2024 Cell Mol Life Sci
| Álvarez-Sánchez A, Grinat J, Doria-Borrell P, Mellado-López M, Pedrera-Alcócer É, Malenchini M, Meseguer S, Hemberger M, Pérez-García V (2024) The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development. Cell Mol Life Sci 81:246. https://doi.org/10.1007/s00018-024-05284-2 |
Alvarez-Sanchez Andrea, Grinat Johanna, Doria-Borrell Paula, Mellado-Lopez Maravillas, Pedrera-Alcocer Erica, Malenchini Marta, Meseguer Salvador, Hemberger Myriam, Perez-Garcia Vicente (2024) Cell Mol Life Sci
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: CRISPR/Cas9 technology, Endoplasmic reticulum stress, Placental Syncytiotrophoblast, Preeclampsia, Trophoblast stem cells, Unfolded protein response • Bioblast editor: Plangger M
Labels: MiParea: Respiration, Genetic knockout;overexpression, Developmental biology
Organism: Mouse
Tissue;cell: Stem cells
Preparation: Intact cells
Coupling state: ET, LEAK, ROUTINE
Pathway: ROX
HRR: Oxygraph-2k
2024-07
