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Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme

Nature volume 400, pages 773–776 (1999)Cite this article

Abstract

Heparin is a sulphated polysaccharide, synthesized exclusively by connective-tissue-type mast cells1 and stored in the secretory granules in complex with histamine and various mast-cell proteases2. 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 positions1,3. The initial modification step, catalysed by the enzyme glucosaminyl N -deacetylase/N -sulphotransferase-2, NDST-2 (4–7), 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.

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Figure 1: Targeted disruption of the NDST-2 locus and establishment of a mutant mouse strain.
Figure 2: Absence of normally sulphated heparin and mast-cell proteases in peritoneal cells from NDST-2 −/− mice.
Figure 3: Absence of normal peritoneal mast cells in NDST-2 −/− mice.
Figure 4: Altered morphology of heparin-containing mast cells.

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Acknowledgements

We thank A. Nagy for R1 ES cells, and P. Ekblom and U. Lindahl for helpful suggestions and support. This work was supported by grants from the Swedish Natural Science Research Council, the Swedish Medical Research Council, the European commission, Polysackaridforskning AB, Gustaf V:s 80-årsfond, Magnus Bergvalls stiftelse, Wibergs stiftelse and Stiftelsen Lars Hiertas minne. E.F. is a member of Uppsala University Transgenic Facility, supported by the Swedish Foundation for Strategic Research.

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  1. Erik Forsberg and Gunnar Pejler: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Cell and Molecular Biology, Box 596

    Erik Forsberg, Maria Ringvall, Carolina Lunderius & Lars Hellman

  2. Department of Medical Biochemistry and Microbiology, Box 582

    Marion Kusche-Gullberg

  3. University of Uppsala, S-751 23, Uppsala, Sweden

    Marion Kusche-Gullberg

  4. Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, Box 575, S-75123, Uppsala, Sweden

    Gunnar Pejler, Bianca Tomasini-Johansson, Inger Eriksson, Johan Ledin & Lena Kjellén

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Correspondence to Lena Kjellén.

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Forsberg, E., Pejler, G., Ringvall, M. et al. Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme. Nature 400, 773–776 (1999). https://doi.org/10.1038/23488

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