Defective Heparan Sulfate Biosynthesis and Neonatal Lethality in Mice LackingN-Deacetylase/N-Sulfotransferase-1

Ringvall, Maria; Ledin, Johan; Holmborn, Katarina; Kuppevelt, Toin van; Ellin, Fredrik; Eriksson, Inger; Olofsson, Anne-Mari; Kjellén, Lena; Forsberg, Erik

doi:10.1074/jbc.c000359200

Cited by 217 publications

(182 citation statements)

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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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“…For example, studies showed that N-deacetylase/N-sulfotransferase-1 (NDST1) is an essential NDSR isozyme in mouse embryonic development, 15 and disruption of NDST1, resulting in severe malformations in the lung. 16 Therefore, miR-149 was likely to affect the expression of the miRNA target gene NDST1 and contribute to the susceptibility of CWP. However, functional characterizations of SNP rs2292832 in miR-149 and its target mRNAs in CWP are warranted.…”

Section: Discussionmentioning

confidence: 99%

Common genetic variants in pre-microRNAs are associated with risk of coal workers' pneumoconiosis

et al. 2009

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microRNAs (miRNAs) are an abundant class of small noncoding RNA molecules thought to be involved in biological functions, including embryonic development, chromosome architecture, cell proliferation and apoptosis. We hypothesized that common variants in the miRNAs are associated with risk of coal workers' pneumoconiosis (CWP). In a case-control study of 496 CWP patients and 513 control subjects frequency matched by exposure years and work types, we genotyped four single-nucleotide polymorphisms (SNPs) (rs2910164, rs2292832, rs11614913 and rs3746444) in pre-miRNAs (miR-146a, miR-149, miR196a2 and miR-499) and assessed the associations with risk of CWP. A significantly increased risk of CWP was found for the miR-149 rs2292832 TT genotype (odds ratio (OR), 1.31; 95% confidence interval (CI), 1.01-1.69), compared with the CT/CC genotypes, and this increased risk was evident among subgroups of those aged X68 years (OR¼1.52, 95% CI¼1.03-2.25), dust exposure X26 years (OR¼1.42, 95% CI¼1.04-1.93) and ever smokers (OR¼1.48, 95% CI¼1.00-2.20). Furthermore, a significant association was observed between the genotypes and patients with stages II and III (OR¼1.50, 95% CI¼1.05-2.14 for stage II, and OR¼3.33, 95% CI¼1.67-6.65 for stage III). These results suggest that miR-149 rs2292832 polymorphism is involved in susceptibility to developing CWP.

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“…Ndst1 mutants show apparently normal lung structure but have major deficiency in surfactant production leading to neonatal lethality. Abnormal dilated lung alveolar spaces have been reported in Sulf2 2/2 mice in which HS 6-O sulfation is altered by the lack of HS sulfatase 2 (Sulf2) (Fan et al, 2000;Li et al, 2003;Lum et al, 2007;Ringvall et al, 2000).…”

Section: Organogenesis In the Absence Of Hs6st1mentioning

confidence: 99%

Systemic inactivation of Hs6st1 in mice is associated with late postnatal mortality without major defects in organogenesis

Izvolsky

Lü

Martin

et al. 2008

Genesis

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Summary: Heparan sulfate (HS) proteoglycans modulate the biological activity of a number of growth factors in development, homeostasis, and cancer. Specific modifications of HS chains by HS biosynthetic enzymes have been implicated in growth factor signaling in multiple aspects of organogenesis. Although the role of HS 6-O-sulfotransferases has been described in processes such as trachea formation in Drosophila and vasculogenesis in zebrafish, little is known about how HS 6-O-sulfotransferases (Hs6st1-3 in mice) influence mouse development. To address this issue, we generated a conditionally mutant Hs6st1 mouse line and then generated mice with systemic inactivation of Hs6st1. Hs6st1-null pups were viable and grossly normal at birth. The lack of obvious abnormalities in lung, liver, and kidney, which express high levels of Hs6st1 during development, suggests that at least during embryonic life, the loss of Hs6st1 function may be compensated for by mechanisms involving other HS modifying enzymes. During early adulthood, however, Hs6st1-null mice failed to thrive and exhibited growth retardation, body weight loss, enlargement of airspaces in the lung and, in some cases, lethality. Our results suggest a potentially critical role for HS 6-O sulfation by Hs6st1 in postnatal processes. genesis 46:8-18,

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Defective Heparan Sulfate Biosynthesis and Neonatal Lethality in Mice LackingN-Deacetylase/N-Sulfotransferase-1

Cited by 217 publications

References 42 publications

Heparin and Heparan Sulfate Biosynthesis

Heparin and Heparan Sulfate Biosynthesis

Common genetic variants in pre-microRNAs are associated with risk of coal workers' pneumoconiosis

Systemic inactivation of Hs6st1 in mice is associated with late postnatal mortality without major defects in organogenesis

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