Mice deficient in heparan sulfate 6-O-sulfotransferase-1 exhibit defective heparan sulfate biosynthesis, abnormal placentation, and late embryonic lethality.
Heparan sulfate (HS) plays critical roles in a variety of developmental, physiological, and pathogenic processes due to its ability to interact in a structure-dependent manner with numerous growth factors that participate in cellular signaling. The divergent structures of HS glycosaminoglycans are the result of the coordinate actions of several N- and O-sulfotransferases, C5-epimerase, and 6-O-endosulfatases. We have shown that 6-O-sulfation of the glucosamine residues in HS are catalyzed by the sulfotransferases HS6ST-1, -2, and -3. To determine the biological and physiological importance of HS6ST-1, we now describe the creation of transgenic mice that lack this sulfotransferase. Most of our HS6ST-1-null mice died between embryonic day 15.5 and the perinatal stage, and those mice that survived were considerably smaller than their wild-type littermates. Some of these HS6ST-1-null mice exhibited development abnormalities, and histochemical and molecular analyses of these mice revealed an approximately 50% reduction in the number of fetal microvessels in the labyrinthine zone of the placenta relative to that in the wild-type mice. Because we observed a modest reduction in VEGF-A mRNA and protein in the tissues of HS6ST-1-null mice, an HS-dependent defect in cytokine signaling probably contributes to increased embryonic lethality and decreased growth. Biochemical studies of the HS chains isolated from various organs of our HS6ST-1-null mice revealed a marked reduction of GlcNAc(6SO(4)) and HexA-GlcNSO(3)(6SO(4)) levels and a reduced ability to bind Wnt2. Thus, despite the presence of three closely related 6-O-sulfotransferase genes in the mouse genome, HS6ST-1 is the primary one used in HS biosynthesis in most tissues.
Habuchi
Hiroko
H
Institute for Molecular Science of Medicine and Laboratory Animal Research Center, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
Nagai
Naoko
N
Sugaya
Noriko
N
Atsumi
Fukiko
F
Stevens
Richard L
RL
Kimata
Koji
K
D000818:Animals; D020964:Embryo Loss / Q000201:enzymology / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006497:Heparan Sulfate / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010920:Placenta / Q000002:abnormalities / Q000098:blood supply / Q000201:enzymology; D010922:Placenta Diseases / Q000201:enzymology / Q000235:genetics*; D010929:Placentation / Q000235:genetics*; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics*; D015238:Sulfotransferases / Q000172:deficiency* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D006497:Heparan Sulfate; D015238:Sulfotransferases; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C485756:Hs6st1 protein, mouse