Mice deficient in heparan sulfate 6-O-sulfotransferase-1

Heparan sulfate chains are initially synthesized on core proteins as linear polysaccharides composed of glucuronic acid-N-acetylglucosamine repeating units and subjected to marked structural modification by sulfation at various places and epimerization of hexuronic acid residues (C5-epimerase) at the Golgi lumen and further by 6-O-desulfation at the cell surface, which generates their characteristic divergent fine structures. This chapter focuses on the biological and physiological functions of 6-O-sulfation in HS and the characterization of the enzymes catalyzing 6-O-sulfation (HS6ST). HS6STs in mammals such as humans and mice comprise of three isoforms (HS6ST-1, -2, and -3) and one alternatively spliced form of HS6ST-2 (HS6ST-2S). Each of these isoforms has distinct substrate preferences, albeit overlapping each other. These HS6ST isoforms are expressed in a spatiotemporally regulated manner in most organs. HS6ST-1-deficient mice are lethal mostly at later embryonic stages and exhibit abnormal angiogenesis in labyrinthine zone of placenta and aberrant lung morphology similar to pulmonary emphysema. These knockout mice also exhibit retinal axon guidance abnormality at the optic chiasm. Other HS6ST-deficient animals reveal various malformations in muscle development and branching morphology of the caudal vein of zebrafish, in tracheal formation of Drosophila, and in axon guidance of ventral nerve cord interneurons of Caenorhabditis elegans. Mouse embryonic fibroblasts prepared from HS6ST-1/HS6ST-2 double knockout mice did produce HS lacking 6-O-sulfation and responded differently to various FGFs dependent signaling.