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- Title
Uridine diphosphate-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase deletion in mice leads to lethal intracerebral hemorrhage during embryonic development.
- 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
- 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.
- Publication
Glycobiology, 2021, Vol 31, Issue 11, p1478
- ISSN
0959-6658
- Publication type
Academic Journal
- DOI
10.1093/glycob/cwab069