Uridine diphosphate-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase deletion in mice leads to lethal intracerebral hemorrhage during embryonic development

Abstract Among the enzymes of the biosynthesis of sialoglycoconjugates, uridine diphosphate-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), catalyzing the first essential step of the sialic acid (Sia) de novo biosynthesis, and cytidine monophosphate (CMP)-Sia synthase (CMAS), activ...

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Veröffentlicht in:Glycobiology (Oxford) 2021-12, Vol.31 (11), p.1478-1489
Hauptverfasser: Wedekind, Henri, Kats, Elina, Weiss, Anna-Carina, Thiesler, Hauke, Klaus, Christine, Kispert, Andreas, Horstkorte, Rüdiger, Neumann, Harald, Weinhold, Birgit, Münster-Kühnel, Anja, Abeln, Markus
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Sprache:eng
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Zusammenfassung:Abstract Among the enzymes of the biosynthesis of sialoglycoconjugates, uridine diphosphate-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), catalyzing the first essential step of the sialic acid (Sia) de novo biosynthesis, and cytidine monophosphate (CMP)-Sia synthase (CMAS), activating Sia to CMP-Sia, are particularly important. The knockout of either of these enzymes in mice is embryonically lethal. While the lethality of Cmas−/− mice has been attributed to a maternal complement attack against asialo fetal placental cells, the cause of lethality in Gne-deficient embryos has remained elusive. Here, we advanced the significance of sialylation for embryonic development through detailed histological analyses of Gne−/− embryos and placentae. We found that Gne−/− embryonic and extraembryonic tissues are hyposialylated rather than being completely deficient of sialoglycans, which holds true for Cmas−/− embryos. Residual sialylation of Gne−/− cells can be explained by scavenging free Sia from sialylated maternal serum glycoconjugates via the lysosomal salvage pathway. The placental architecture of Gne−/− mice was unaffected, but severe hemorrhages in the neuroepithelium with extensive bleeding into the cephalic ventricles were present at E12.5 in the mutants. At E13.5, the vast majority of Gne−/− embryos were asystolic. This phenotype persisted when Gne−/− mice were backcrossed to a complement component 3-deficient background, confirming distinct pathomechanisms of Cmas−/− and Gne−/− mice. We conclude that the low level of sialylation observed in Gne−/− mice is sufficient both for immune homeostasis at the fetal–maternal interface and for embryonic development until E12.5. However, formation of the neural microvasculature is the first critical process, depending on a higher degree of sialylation during development of the embryo proper.
ISSN:1460-2423
1460-2423
DOI:10.1093/glycob/cwab069