Defective heparan sulfate biosynthesis and neonatal lethality in mice lacking N-deacetylase/N-sulfotransferase-1

Heparan sulfate is a sulfated polysaccharide present on most cell surfaces and in the extracellular matrix. In vivo functions of heparan sulfate can b e studied in mouse strains lacking enzymes involved in the biosynthesis of heparan sulfate. Glucosaminyl N-deacetylase/N-suLfotransferase (NDST) catal yzes the first modifying step in the biosynthesis of the polysaccharide. Th is bifunctional enzyme occurs in several isoforms. We here report that targ eted gene disruption of NDST-1 in the mouse results in a structural alterat ion of heparan sulfate in most basement membranes as revealed by immunohist ochemical staining of fetal tissue sections using antibodies raised against heparan sulfate. Biochemical analysis of heparan sulfate purified from fib roblast cultures, lung, and liver of NDST-1-deficient embryos demonstrated a dramatic reduction in N-sulfate content. Most NDST-1-deficient embryos su rvive until birth; however, they turn out to be cyanotic and die neonatally in a condition resembling respiratory distress syndrome. In addition, a mi nor proportion of NDST-1 deficient embryos die during the embryonic period. The cause of the embryonic lethality is still obscure, but incompletely pe netrant defects of the skull and the eyes have been observed.