Terminal α1-2 Fucosyl Glycoconjugates Synthesized by FUT1: A Novel Key Regulator Function in Cell-Fate Decision During Early Development

Summary: The composition of cell surface glycoconjugates is set by controlled glycosyltransferase genes, whose function, in the context of cell fate decisions, is poorly understood. Using a human pluripotent cell (hPC)-based differentiation model, we have uncovered a critical function in the reduction of α1-2 fucosyltransferase (FUT1)—a glycosyltransferase catalyzing the synthesis of fucosylated glycoconjugates in α1-2 linkage—in promoting the acquisition of germ layer cell identity. We show that a FUT1 loss of function leads to the induction of lateral mesoderm gene expression, while a FUT1 gain of function prevents lateral mesoderm commitment and impairs endoderm and ectoderm fate specification, such that FUT1-overexpressing hESCs do not differentiate into cardiomyocyte lineages. Analysis of single-cell RNA-seq in mouse embryos (E5.5–E7.5) and embryo staining depict a spatiotemporal pattern of FUT1 activity, first in posterior and then in anterior-distal epiblast cells and later in the restricted region of the ectoderm and endoderm. Notably, fucosyltransferase-2 (FUT2), which acts similar to FUT1 and has been deemed indistinguishable from it, does not add α1-2 fucosyl residues to glycoconjugates instead of FUT1. According to molecular fate maps of known germ-layer markers, FUT1 is expressed in epiblast cells that acquired different layer potency than FUT2. These findings highlight an exclusive function of FUT1 and its synthesized α1-2 fucosylated glycoconjugates in deriving lineage specification and prompt a revision to the functionality of FUT1, in comparison to FUT2, during development.