The molecular phenotype of heparan sulfate in the Hs2st(-/-) mutant mouse

Heparan sulfate (HS) is a co-receptor for a number of growth factors, morph ogens, and adhesion proteins. HS biosynthetic modifications may determine t he strength and outcome of HS-ligand interactions. We previously described the phenotype of mice with a gene-trap mutation in Hs2st, encoding the key HS 2-O-sulfotransferase enzyme in HS polymer modification. In contrast to t he early developmental failure of embryos lacking HS, the onset of abnormal ities in the Hs2st(-/-) mice occurs only after midgestation, the most drama tic being the complete failure of kidney development. Uronate 2-O-sulfates were not detected in the mutant HS, indicating a complete loss of function of Hs2st. However, the domain structure of the mutant HS is conserved, and compensatory increases in N- and 6-O-sulfation maintain the overall charge density. The apparent affinities of the mutant HS for hepatocyte growth fac tor/scatter factor and fibronectin were unchanged but were reduced for fibr oblast growth factor-1 and -2. Surprisingly, the Hs2st(-/-) cells were able to mount an apparently normal signaling response to fibroblast growth fact or-1 and -2 as well as to hepatocyte growth factor/scatter factor.