Terminal Alpha1,2-fucosyl glycoconjugates synthesized by FUT1: A novel key regulator function in cell-fate decisions during early development

The embryonic cell surface is rich in glycosphingolipids (GSLs), the subsets of which can change during differentiation. However, the reasons for GSL subgroup variation during early embryogenesis remain elusive. We combined genomic approaches, flow cytometry, confocal imaging, and transcriptomic data analysis and found that alpha1,2- fucosylated GSLs control the differentiation of human pluripotent cells (hPCs) into germ layer tissues. Overexpression of alpha1,2-fucosylated GSLs has been found to disrupt hPC differentiation into mesodermal and endodermal cell lineages as well as to reduce the potential for cell differentiation into cardiomyocytes, while reduction of alpha1,2-fucosylated groups results in hPC differentiation and mesoderm commitment when cells are exposed to external signals. We found bone morphogenetic protein 4 (BMP4), which is a mesodermal gene inducer, to be a suppressor factor of alpha1,2-fucosylated GSL expression. Overexpression of alpha1,2-fucosylated GSLs dampens many early mesodermal genes, specifically impairing Suppressor of Mothers Against Decapentaplegic (SMAD) activation, despite the presence of BMP4, suggesting that alpha-fucosyl end groups are BMP signaling pathway targets and regulators. As well, despite the presence of BMP4, an absence of alpha1,2-fucosylated GSLs in early/late mesoderm and primitive streak stage of mouse embryos was found, which is consistent with the results of hPCs. Based on these findings, we identified a subset of alpha1,2-fucosylated GSLs that may regulate early cell-fate decisions and embryo development through modulation of cell signaling.