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

Forsberg, Erik; Pejler, Gunnar; Ringvall, Maria; Lunderius, Carolina; Tomasini-Johansson, Bianca R.; Kusche-Gullberg, Marion; Eriksson, Inger; Ledin, Johan; Hellman, Lars; Kjellén, Lena

doi:10.1038/23488

Cited by 439 publications

(423 citation statements)

References 26 publications

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“…In contrast, the ratios of the N -deacetylation and N -sulfation activities between NDST-1 and -2 were similar (72). Notably, mice carrying a targeted disruption of NDST-2 are unable to synthesize heparin but can produce HS (73,74), whereas those of NDST-1 synthesize lowsulfated variant of HS resulting in embryonic lethality (75,76). The NDST isoforms have distinct expression levels in different mouse tissues (72).…”

Section: Biosynthetic Events Modifiying the Glycosylaminoglycan Backbonementioning

confidence: 88%

Heparin and Heparan Sulfate Biosynthesis

2002

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SummaryHeparan sulfate is one of the most informationally rich biopolymers in Nature. Its simple sugar backbone is variously modified to different degrees depending on the cellular conditions. Thus, it matures to have an enormously complicated structure, which most likely exhibits a considerable number of unique overlapping sequences with peculiar sulfation profiles. Such sequences are recognized by specific complementary proteins, which form a huge group of "heparin-binding proteins," and the sugar sequences in turn support unique functions of the respective proteins through specific interactions. The heparan sulfate sequences are not directly encoded by genes, but are created by elaborate biosynthetic mechanisms, which ensure the generation of these indispensable sequences. In heparan sulfate biosynthesis, the tetrasaccharide sequence (GlcAGal-Gal-Xyl-), designated the protein linkage region, is first assembled on a specific Ser residue at the glycosaminoglycan attachment site of a core protein. A heparan sulfate chain is then polymerized on this fragment by alternate additions of GlcNAc and GlcA through the actions of glycosyltransferases with overlapping specificities encoded by the tumor suppressor EXT family genes. Then follow various modifications by N-deacetylation and N-sulfation of glucosamine, C5-epimerization of GlcA and multiple O-sulfations of the component sugars. Recent studies have achieved purification of several, and molecular cloning of most, of the enzymes responsible for these reactions. Some of these enzymes are bifunctional. The availability of cDNA probes has facilitated elucidation of the crystal structures for two of the biosynthetic enzymes, demonstration of their intracellular location, and their occurrence in complexes to achieve rapid and efficient synthesis of complex sugar sequences. Genomic structure and transcript analysis have shown the existence of multiple isoforms for most of the sulfotransferases. Many aspects of the heparan sulfate biosynthetic scheme are shared by the structural analog heparin, which is synthesized in mast cells and some other mammalian cells and is several-fold higher degree of polymerization and more extensive modification than heparan sulfate.

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Section: Biosynthetic Events Modifiying the Glycosylaminoglycan Backbonementioning

confidence: 88%

Heparin and Heparan Sulfate Biosynthesis

2002

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“…Ndst2 −/− and Srgn −/− mast cells shared several characteristics, such as decreased storage of granule proteases with Hdc −/− mast cells and it was concluded that major defects in granule maturation in Ndst2 −/− and Srgn −/− cells should occur at the posttranslational levels; impaired accumulation of sulfated proteoglycans might lead to instability of the granule proteases in Ndst2 −/− and Srgn −/− mast cells. Histamine contents in pMCs of Hdst2 −/− and Srgn −/− mice were found to be significantly decreased [23,25], although it remains unknown whether expression of the Hdc gene is suppressed or granule storage of histamine is impaired in these cells due to the absence of sulfated proteoglycans. A decrease in histamine synthesis may also be involved in the aberrant granule maturation in Hdst2 −/− and Srgn −/− mast cells.…”

Section: Discussionmentioning

confidence: 99%

Histamine synthesis is required for granule maturation in murine mast cells

et al. 2013

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Mast cells are the major sources of histamine, which is released in response to immunological stimulations. The synthesis of histamine is catalyzed by histidine decarboxylase (HDC). Previous studies have shown that Hdc −/− mast cells exhibit aberrant granule morphology with severely decreased granule content. Here, we investigated whether the histamine synthesized in mast cells regulates the granule maturation of murine mast cells. Several genes, including those encoding granule proteases and enzymes involved in heparin biosynthesis, were downregulated in Hdc −/− peritoneal mast cells. Impaired granule maturation was also found in Hdc −/− BM-derived cultured mast cells when they were cocultured with fibroblasts in the presence of c-kit ligand. Exogenous application of histamine and several H 4 receptor agonists restored the granule maturation of Hdc −/− cultured mast cells. However, the maturation of granules was largely normal in Hrh4 −/− peritoneal mast cells. Depletion of cellular histamine with tetrabenazine, an inhibitor of vesicular monoamine transporter-2, did not affect granule maturation. In vivo experiments with mast cell deficient Kit W /Kit W-v mice indicated that the expression of the Hdc gene in mast cells is required for granule maturation. These results suggest that histamine promotes granule maturation in mast cells and acts as an proinflammatory mediator. [6,7]. In a mouse mastocytoma P-815 cells, caspase-9-mediated cleavage results in enzymatic activation of HDC [8]. KeywordsWe have explored novel functions of histamine using a mouse strain lacking the Hdc gene. In the first report of Hdc −/− mice, we noticed that peritoneal mast cells (pMCs) and skin mast cells exhibited an aberrant morphology with severely decreased granule contents [9]. Although several studies indicated that mast cells express specific histamine receptors, it remains unknown how histamine affects the nature of mast cells. On the other hand, positive modulators for growth and differentiation of mast cells, such as IL-3 and c-kit ligand (Kitl), were found to induce a transient increase in histamine synthesis [10,11], raising a possibility that histamine is involved in the process of mast cell maturation. We hypothesized that newly synthesized histamine may play a critical role in granule maturation of mast cells in an autocrine fashion. We, here, took two different approaches to investigate the mechanism underlying the histamine-mediated promotion of granule maturation of mast cells; an in vitro approach using a mast cell fibroblast coculture model and an in vivo one using the mast cell reconstitution system with mast cell deficient Kit W /Kit W-v mice. This study proposes a novel function of histamine in mast cell biology. Results Characterization of the pMCs in Hdc −/− miceWe previously reported that the cutaneous and pMCs of Hdc −/− mice demonstrate aberrant granules with severely decreased contents [9]. pMCs in Hdc −/− mice were poorly-stained with Safranin-O and acidic Toluidine blue, compared with those in WT mice (Fi...

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“…This is critical because sulfation patterns within HS chains govern their ability to bind and influence the activity of soluble and matrix proteins including key factors, for example, members of the fibroblast growth factor (FGF) family [8,9]. Mice mutant for many components of the biosynthetic pathway have demonstrated that the majority of modifications are critical for successful development [10][11][12][13]. HS-deficient mice were created by deleting either Ext1 or Ext2 [14,15], and the pregastrulation lethality of the phenotypes indicates a critical need for HS in tissue organization and migration.…”

Section: Introductionmentioning

confidence: 99%

Specific Glycosaminoglycans Modulate Neural Specification of Mouse Embryonic Stem Cells

et al. 2011

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Mouse embryonic stem (mES) cells express a low sulfated form of heparan sulfate (HS). HS chains displayed by ES cells and their progeny become more complex and more sulfated during progression from pluripotency to neuroectodermal precursors. Sulfated epitopes are important for recognition and binding of a variety of ligands including members of the fibroblast growth factor (FGF) family. We demonstrated previously that mES cells lacking HS cannot undergo neural specification but this activity can be recovered by adding soluble heparin, a highly sulfated glycosaminoglycan (GAG). Therefore, we hypothesized that soluble GAGs might be used to support neural differentiation of HS competent cells and that the mechanisms underlying this activity might provide useful information about the signaling pathways critical for loss of pluripotency and early lineage commitment. In this study, we demonstrate that specific HS/heparin polysaccharides support formation of Sox1 1 neural progenitor cells from wild-type ES cells. This effect is dependent on sulfation pattern, concentration, and length of saccharide. Using a selective inhibitor of FGF signal transduction, we show that heparin modulates signaling events regulating exit from pluripotency and commitment to primitive ectoderm and subsequently neuroectoderm. Interestingly, we were also able to demonstrate that multiple receptor tyrosine kinases were influenced by HS in this system. This suggests roles for additional factors, possibly in cell proliferation or protection from apoptosis, during the process of neural specification. Therefore, we conclude that soluble GAGs or synthetic mimics could be considered as suitable low-cost factors for addition to ES cell differentiation regimes. STEM CELLS 2011;29:629-640 Disclosure of potential conflicts of interest is found at the end of this article.

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

Cited by 439 publications

References 26 publications

Heparin and Heparan Sulfate Biosynthesis

Heparin and Heparan Sulfate Biosynthesis

Histamine synthesis is required for granule maturation in murine mast cells

Specific Glycosaminoglycans Modulate Neural Specification of Mouse Embryonic Stem Cells

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