Terminal α1,2-fucosylation of glycosphingolipids by FUT1 is a key regulator in early cell-fate decisions

• Published in: EMBO reports 2024-10, Vol.25 (10), p.4433-4464
• Main Authors: Chen, Saray, Hayoun-Neeman, Dana, Nagar, Michal, Pinyan, Sapir, Hadad, Limor, Yaacobov, Liat, Alon, Lilach, Shachar, Liraz Efrat, Swissa, Tair, Kryukov, Olga, Gershoni-Yahalom, Orly, Rosental, Benyamin, Cohen, Smadar, Lichtenstein, Rachel G
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Bone Morphogenetic Protein 4 - metabolism; Cell Differentiation - genetics; Cell Lineage - genetics; EMBO20; EMBO34; EMBO37; Embryo, Mammalian - metabolism; Embryonic Development - genetics; Fucose - metabolism; Fucosyltransferases - genetics; Fucosyltransferases - metabolism; Galactoside 2-alpha-L-fucosyltransferase; Gene Expression Regulation, Developmental; Germ Layers - metabolism; Glycosphingolipids - metabolism; Humans; Life Sciences; Mesoderm - metabolism; Mice; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Signal Transduction
• ISSN: 1469-3178; 1469-221X; 1469-3178
• DOI: 10.1038/s44319-024-00243-1

The embryonic cell surface is rich in glycosphingolipids (GSLs), which change during differentiation. The reasons for GSL subgroup variation during early embryogenesis remain elusive. By combining genomic approaches, flow cytometry, confocal imaging, and transcriptomic data analysis, we discovered that α1,2-fucosylated GSLs control the differentiation of human pluripotent cells (hPCs) into germ layer tissues. Overexpression of α1,2-fucosylated GSLs disrupts hPC differentiation into mesodermal lineage and reduces differentiation into cardiomyocytes. Conversely, reducing α1,2-fucosylated groups promotes hPC differentiation and mesoderm commitment in response to external signals. We find that bone morphogenetic protein 4 (BMP4), a mesodermal gene inducer, suppresses α1,2-fucosylated GSL expression. Overexpression of α1,2-fucosylated GSLs impairs SMAD activation despite BMP4 presence, suggesting α-fucosyl end groups as BMP pathway regulators. Additionally, the absence of α1,2-fucosylated GSLs in early/late mesoderm and primitive streak stages in mouse embryos aligns with the hPC results. Thus, α1,2-fucosylated GSLs may regulate early cell-fate decisions and embryo development by modulating cell signaling. Synopsis The variation in glycosphingolipids (GSLs) during embryogenesis influences human pluripotent cel differentiation. Specifically, α1,2-fucosylated GSLs control hPC differentiation into germ layers, impacting mesodermal lineage formation through BMP pathway regulation. hESC differentiation towards the three germ layers depends on the levels of α1-2 fucosyltransferase-1 (FUT1). High expression of α1,2-fucosyl GSLs compromises hESC differentiation into mesodermal and cardiac lineages. Overexpression of α1,2-fucosyl GSLs impairs SMAD activation, suggesting they are BMP pathway regulators. FUT1 and FUT2 have different functionalities during early embryonic development. The variation in glycosphingolipids (GSLs) during embryogenesis influences human pluripotent cell differentiation. Specifically, α1,2-fucosylated GSLs control hPC differentiation into germ layers, impacting mesodermal lineage formation through BMP pathway regulation.