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Impaired mast cell development in N-deacetylase/N-sulfotransferase deficient embryonic stem cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-94256OAI: oai:DiVA.org:uu-94256DiVA: diva2:168044
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2015-05-29Bibliographically approved
In thesis
1. Heparan Sulfate and Development: A Study of NDST Deficient Mice and Embryonic Stem Cells
Open this publication in new window or tab >>Heparan Sulfate and Development: A Study of NDST Deficient Mice and Embryonic Stem Cells
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate (HS) proteoglycans consist of sulfated HS chains covalently bound to core proteins. They are ubiquitously expressed, on the cell surface and in the extracellular matrix, throughout the body. During biosynthesis the HS chain is modified to generate a highly variable pattern of sulfated residues, able to interact with a wide variety of ligands, such as growth factors, morphogens and extracellular matrix molecules. The presence of HS proteoglycans is crucial during various developmental processes as they are involved in generation of morphogen gradients and influence the function of several growth factor pathways essential for tissue assembly and differentiation.

In this thesis the phenotypes of two mouse strains, deficient in different isoforms of the HS biosynthetic enzyme N-deacetylase/N-sulfotransferase (NDST) have been analyzed. In addition, NDST deficient embryonic stem (ES) cells have been analyzed with regard to HS structure and differentiation capacity. Mice deficient in NDST1 die peri-natally. The embryos display an overall low-sulfated HS and several developmental defects, with a lung phenotype as the predominant cause of death. Mice deficient in NDST2 lack sulfated heparin in connective tissue type mast cells while HS structure is unaltered. These results indicate that NDST1 is the isoform mainly responsible for HS biosynthesis during development. However, NDST1/2 deficient embryos do not survive beyond E5.5 and have a greatly disturbed morphology, suggesting that NDST2 has an essential role during early embryonic development. HS synthesized by NDST1/2 deficient ES cells had a total lack of N-sulfate groups while, interestingly, about half of the 6-O-sulfate groups remained. This result was unexpected since 6-O-sulfotransferases have been thought to be strictly dependent on N-sulfate groups for substrate recognition. Further characterization of the NDST1/2 deficient ES cells during in vitro differentiation demonstrated that the expression pattern of markers for all three germ layers was disturbed. In addition, it was demonstrated that NDST1 is not needed for mast cell development, that lack of NDST2 results in abnormal mast cells and that no mast cells is formed from NDST1/2 deficient ES cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 132
Keyword
Cell and molecular biology, heparan sulfate, proteoglycan, biosynthesis, N-deacetylase/N-sulfotransferase, NDST, gene targeting, embryonic development, lung development, mast cells, Cell- och molekylärbiologi
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-6743 (URN)91-554-6520-X (ISBN)
Public defence
2006-04-29, B42, The Biomedical Center, Husarg. 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2015-09-04Bibliographically approved

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Holmborn, KatarinaKjellén, Lena

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