Disease relevance of Ndst2

• We can conclude that although NDST-2(-/-) mice demonstrate an altered response in P(if) after mast cell activation, there was no similar alteration after neurogenic inflammation [1].
• A similar, high degree of thrombosis was also observed in B16 tumors grown in transgenic NDST-2 knockout mice bearing a targeted disruption in the gene coding for mast cell heparin synthesis [2].

High impact information on Ndst2

• 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 [3].
• Here we report that mice carrying a targeted disruption of the gene encoding NDST-2 are unable to synthesize sulphated heparin [3].
• GA binding protein (GABP) bound the GGAA motif and increased the amount of NDST-2 transcript [4].
• Heparan sulfate synthesized by mouse embryonic stem cells deficient in NDST1 and NDST2 is 6-O-sulfated but contains no N-sulfate groups [5].
• Using a high throughput heparan sulfate (HS) isolation and characterization protocol, we have analyzed HS structure in several tissues from mice/mouse embryos deficient in HS biosynthesis enzymes (N-deacetylase/N-sulfotransferase (NDST)-1, NDST-2, and C5-epimerase, respectively) and in mice lacking syndecan-1 [6].

Biological context of Ndst2

• Using high-speed UV confocal laser scanning microscopy, aberrant Ca2+ kinetics were observed in NDST-1-/- myotubes, but not in NDST-2-/- or heterozygous myotubes [7].
• Accelerated growth and blood clotting were also observed in tumor-bearing mice treated with heparinase I enzyme to destroy endogenous mast cell heparin and in NDST-2 knockout mice in which there is a targeted disruption in the gene coding for mast cell heparin synthesis [8].
• The deduced amino acid sequence shows 70% and 65% amino acid identity to that of hNDST1 and NDST2, respectively [9].
• Human NDST3 (hNDST3) has a nucleotide sequence homologous but not identical to hNDST1 and NDST2 [9].

Anatomical context of Ndst2

• Here, we report on the effects of NDST deficiency on Ca2+ kinetics in myotubes from NDST-1- and NDST-2-deficient mice, indicating a novel role for heparan sulfate in skeletal muscle physiology [7].
• To examine a possible role of connective tissue mast cells (CTMCs) in these inflammatory responses, we used mice with dysfunctional CTMCs due to lack of the N-deacetylase/N-sulfotransferase-2 enzyme (NDST-2(-/-)) [1].

Associations of Ndst2 with chemical compounds

• The corresponding NDST-2-/- cells produced highly sulphated CS only [10].

Enzymatic interactions of Ndst2

• Further experiments showed that the degradation of fibronectin observed in cell cultures from NDST-2(+/+) mice was catalyzed by mast cell chymase in a strongly heparin-dependent manner [11].

Regulatory relationships of Ndst2

• Plasminogen was activated to plasmin at an apparently higher rate in peritoneal cells from NDST-2 null mice than in the normal controls [12].

Other interactions of Ndst2

• Western blot analysis showed the presence of fibronectin degradation products in cell cultures from normal mice, which were absent in cultures from NDST-2(-/-) animals [11].
• At least two alternatively spliced forms of NDST2 differing in their 5'-UTRs exist, and two forms of NDST4 arise from alternative transcriptional start sites [13].
• Here we show that NDST-2+/+ bone marrow-derived mast cells cultured in the presence of IL-3 synthesise, in addition to highly sulphated chondroitin sulphate (CS), small amounts of equally highly sulphated heparin-like polysaccharide [10].
• The NDST-2(-/-) mice show reduced levels of various mast cell mediators such as histamine and various heparin-binding mast cell proteases, including chymases, tryptases, and carboxypeptidase A. In this work we have addressed the possible functional consequences of the lack of sulfated heparin [11].

Analytical, diagnostic and therapeutic context of Ndst2

• PPE was increased 300% after treatment with C48/80 in NDST-2(+/+) mice, whereas there was no increase in PPE in NDST-2(-/-) mice [1].
• Heparin-deficient mice, generated by gene targeting of N-deacetylase/N-sulfotransferase-2 (NDST-2), display severe mast cell defects, including an absence of stored mast cell proteases [10].
• Northern blot analysis revealed mRNA expression of CPA, mMCP-5 and mMCP-6 in both wild-type and NDST-2-/- cells [10].
• The NDST-2 mRNA was detected by in situ hybridization in the skin mast cells of +/+ and tg/tg mice, but not in the skin mast cells of mi/mi mice [4].

References