P25. Specific expression of heparan sulfate glycosaminoglycan chains is crucial for local distribution of FGF signaling during mammalian embryogenesis

Abstract

Heparan sulfate (HS) proteoglycans comprising HS glycosaminoglycan chains (HS chains) and core proteins have been functionally implicated as co-receptors for multiple growth factors in the cell surface and extracellular matrix. However, the precise mechanisms by which HS chains regulate the activity of growth factors in complex mammalian morphogenetic processes remain to be elucidated. Here, we identified the transgene insertion allele of Ext2, a gene causative of multiple hereditary exostoses that catalyzes the elongation of HS chains. Marker expression analyses of Ext2-deficient embryos revealed that HS chains are essential for the response to Fibroblast growth factor (FGF) signaling and, in particular, for the local distribution of FGF ligands in the extraembryonic ectoderm. Moreover, the expression of HS chains attached to the cell surface is specific to those areas in which FGF signaling is potentially active. Additional fine mosaic studies with single-cell resolution involving chimeras suggested that the expression of cell surface-attached HS-chains is crucial for early embryonic development. Given that 22 FGF ligands, 4 FGF receptors, and 12 membrane-associated core proteins are redundantly expressed, we propose that the spatially and temporally localized expression of HS-chains attached to cell surfaces also contributes to FGF signaling distribution during mammalian morphogenesis.