The Molecular Phenotype of Heparan Sulfate in theHs2st−/− Mutant Mouse

Abstract

Heparan sulfate (HS) is a co-receptor for a number of growth factors, morphogens, and adhesion proteins. HS biosynthetic modifications may determine the 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 the early developmental failure of embryos lacking HS, the onset of abnormalities in the Hs2st ؊/؊ mice occurs only after midgestation, the most dramatic 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 factor/scatter factor and fibronectin were unchanged but were reduced for fibroblast growth factor-1 and -2. Surprisingly, the Hs2st ؊/؊ cells were able to mount an apparently normal signaling response to fibroblast growth factor-1 and -2 as well as to hepatocyte growth factor/scatter factor.Many key events in embryogenesis depend on growth and differentiation factors that specify lineage commitment and control the expansion and morphogenesis of maturing cell populations. It is becoming increasingly apparent that many of these factors have a requirement for, or have their activity modulated by, heparan sulfate proteoglycans (HSPGs).

Heparin and Heparan Sulfate Biosynthesis

“…Surprisingly, the HS2ST-deficient mouse cells mounted an apparently normal signaling response to several growth factors despite the fact that at least some growth factors require a 2-O-sulfate group for their binding to HS. Compensatory increases in N -and 6-O-sulfation were observed for the HS chains of these cells (86) and may explain why a wide range of tissues except the kidney are affected only mildly (85). These results appear to suggest that a hitherto unknown biosynthetic mechanism exists, by which a structurally unusual HS is synthesized in the mutant cells to fulfill some, but not all, of functions of normal HS.…”

Impairment of glycosaminoglycan synthesis in mucopolysaccharidosis type IIIA cells by using siRNA: a potential therapeutic approach for Sanfilippo disease

“…In fact, it was reported that mutations in exostosin 1 (EXT1), exostosin 2 (EXT2), [17][18][19] N-deacetylase/N-sulfotransferase 1 (NDST1), N-deacetylase/N-sulfotransferase 2 (NDST2), [20][21][22] heparan sulfate 2-O-sulfotransferase (HS2ST), heparan sulfate 3-O-sulfotransferase-1 (HS3ST1), [23][24][25][26] heparan sulfate 6-O-sulfotransferase-1 (HS6ST1) 27 and heparan sulfate C5 epimerase (GLCE) 28 genes caused serious defects in mice and/or humans. Therefore, a significant decrease in expression of one of these genes might be potentially dangerous for patients.…”

Targeted Disruption of a Murine Glucuronyl C5-epimerase Gene Results in Heparan Sulfate Lacking l-Iduronic Acid and in Neonatal Lethality

“…HS synthesized by mice deficient in N-deacetylase/N-sulfotransferase isoform 1 (NDST-1) is low in N-sulfate, hence in IdoA (sulfated and non-sulfated) and total O-sulfate compared with (20), whereas the overall content of IdoA is similar to that of wild type HS (21). 2 The Hs2st Ϫ/Ϫ mice further show several skeletal abnormalities indistinguishable from those seen in Hsepi Ϫ/Ϫ animals (17,18).…”