Uridine diphosphate-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase deletion in mice leads to lethal intracerebral hemorrhage during embryonic development. (5th July 2021)

• Record Type: Journal Article
• Authors: Wedekind, Henri; Kats, Elina; Weiss, Anna-Carina; Thiesler, Hauke; Klaus, Christine; Kispert, Andreas; Horstkorte, Rüdiger; Neumann, Harald; Weinhold, Birgit; Münster-Kühnel, Anja; Abeln, Markus
• Is Part Of: Glycobiology. Volume 31:Number 11(2021)
• Page Start: 1478
• Page End: 1489
• Publication Date: 2021-07-05
• Subjects: angiogenesis -- embryogenesis -- GNE -- placenta -- sialic acid; Glycoproteins -- Periodicals; Glycolipids -- Periodicals; Glycoconjugates -- Periodicals; 572.567
• DOI: 10.1093/glycob/cwab069
• Languages: English
• ISSNs: 0959-6658

Abstract

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.