Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme.
Heparin is a sulphated polysaccharide, synthesized exclusively by connective-tissue-type mast cells and stored in the secretory granules in complex with histamine and various mast-cell proteases. Although heparin has long been used as an antithrombotic drug, endogenous heparin is not present in the blood, so it cannot have a physiological role in regulating blood coagulation. The biosynthesis of heparin involves a series of enzymatic reactions, including sulphation at various positions. The initial modification step, catalysed by the enzyme glucosaminyl N-deacetylase/N-sulphotransferase-2, NDST-2, is essential for the subsequent reactions. Here we report that mice carrying a targeted disruption of the gene encoding NDST-2 are unable to synthesize sulphated heparin. These NDST-2-deficient mice are viable and fertile but have fewer connective-tissue-type mast cells; these cells have an altered morphology and contain severely reduced amounts of histamine and mast-cell proteases. Our results indicate that one site of physiological action for heparin could be inside connective-tissue-type mast cells, where its absence results in severe defects in the secretory granules.
Forsberg
E
E
Department of Cell and Molecular Biology, University of Uppsala, Sweden.
Pejler
G
G
Ringvall
M
M
Lunderius
C
C
Tomasini-Johansson
B
B
Kusche-Gullberg
M
M
Eriksson
I
I
Ledin
J
J
Hellman
L
L
Kjellén
L
L
D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D053818:Chymases; D003433:Crosses, Genetic; D005260:Female; D018390:Gene Targeting; D005838:Genotype; D006493:Heparin / Q000096:biosynthesis* / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009504:Neutrophils / Q000276:immunology; D010537:Peritoneum / Q000473:pathology; D012697:Serine Endopeptidases / Q000378:metabolism; D013234:Stem Cells; D013431:Sulfates / Q000378:metabolism; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D013431:Sulfates; D007073:Immunoglobulin E; D006493:Heparin; C491855:Ndst2 protein, mouse; D015238:Sulfotransferases; D012697:Serine Endopeptidases; D053818:Chymases; D000581:Amidohydrolases