Divergent roles of heparan sulfate in regulation of FGF signaling during mammalian embryogenesis

Abstract

Heparan sulfate proteoglycans, composed of heparan sulfate (HS) glycosaminoglycan chains and core proteins, are distributed at the cell surface as well as in the extracellular matrix (ECM). HS chains play crucial yet divergent roles in regulation of fibroblast growth factor (FGF) signaling extracellularly: as an essential cofactor for ligand-receptor dimerization at the cell surface, positive and negative modulators of stable dimer formation, as a key mediator of active movement of ligands, and as a spatial barrier for passive diffusion in the ECM. These divergent functions are mediated by the local HS structures, for example, chain length and sulfation level, and by the spreading of unanchored HS chains after enzymatic cleavage by proteinases and heparanases. In this way, FGF signaling activity modified by HS participates in multiple cellular processes including cell proliferation, differentiation, survival, and migration during embryonic development. In this chapter, we highlight the essential and cell nonautonomous roles of the cell-surface HS in activation of FGF signaling during mouse extra-embryonic ectoderm development.