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Abnormal mast cells in mice deficient in a heparin-sythesizing enzyme
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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1999 (English)In: Nature, Vol. 400, 773-776 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
1999. Vol. 400, 773-776 p.
URN: urn:nbn:se:uu:diva-91697OAI: oai:DiVA.org:uu-91697DiVA: diva2:164516
Available from: 2004-04-23 Created: 2004-04-23 Last updated: 2011-06-28Bibliographically approved
In thesis
1. Functions of Heparan Sulfate During Mouse Development: Studies of Mice with Genetically Altered Heparan Sulfate Biosynthesis
Open this publication in new window or tab >>Functions of Heparan Sulfate During Mouse Development: Studies of Mice with Genetically Altered Heparan Sulfate Biosynthesis
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate (HS) is a ubiquitous polysaccharide on the cell surface and in the extracellular matrix. HS is an important actor in the regulation of cell signaling, especially in the developing embryo. In combination with cell culture and biochemical experiments, in vivo studies of genetically modified animals have pointed out the sulfation pattern of HS as highly important for binding of ligands, their receptors and other signaling modulators.

The sulfation pattern of an HS chain is gained by several modifying steps, performed by multiple enzymes during biosynthesis in the Golgi apparatus. By alterations of sulfation pattern, and the amount of sulfate groups, a cell can regulate the binding properties of its HS to different molecules. The most highly sulfated form of HS is called heparin, and can only be found intracellularly in mast cells.

This thesis describes the phenotypes and the alterations in HS/heparin biosynthesis of two genetically modified mouse strains deficient in N-deacetylase/N-sulfotransferase-1 (NDST1) and -2 (NDST2) respectively. We have found NDST1 to be important for correct sulfation of HS and that NDST2 is crucial in heparin biosynthesis. NDST2 deficient mice completely lack heparin and therefore have a severe mast cell phenotype. NDST1 deficient mice produce undersulfated HS and show several developmental disturbances. Some NDST1 embryos die in utero while the rest die neonatally due to breathing difficulties. Defect brain, eye and skeletal development has also been observed while some organs, such as the liver, appear to be largely unaffected. Several phenotypes are similar to defects seen in other mouse strains with impaired fibroblast growth factor and bone morphogenetic protein signaling, among others. This suggests the phenotypes of NDST1 deficient embryos to be of a multi factorial origin, in complete accordance to the many signaling pathways HS is suggested to modulate.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 63 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1347
Developmental biology, embryonic development, gene targeting, lung development, ossification, heparan sulfate, heparin, N-deacetylase/N-sulfaotransferase, NDST, proteoglycan, morphogen, biosynthesis, Utvecklingsbiologi
National Category
Developmental Biology
urn:nbn:se:uu:diva-4244 (URN)91-554-5955-2 (ISBN)
Public defence
2004-05-15, B 42, BMC, Husargatan 3, Uppsala, 13:15
Available from: 2004-04-23 Created: 2004-04-23Bibliographically approved

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Ringvall, MariaKjellén, Lena
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