Sialylation is essential for early development in mice

Abstract

Sialic acids are widely expressed as terminal carbohydrates on glycoconjugates of eukaryotic cells. Sialylation is crucial for a variety of cellular functions, such as cell adhesion or signal recognition, and regulates the biological stability of glycoproteins. The key enzyme of sialic acid biosynthesis is the bifunctional UDP-N-acetylglucosamine-2-epimerase͞N-acetylmannosamine kinase (UDP-GlcNAc 2-epimerase), which catalyzes the first two steps of sialic acid biosynthesis in the cytosol. We report that inactivation of the UDP-GlcNAc 2-epimerase by gene targeting causes early embryonic lethality in mice, thereby emphasizing the fundamental role of this bifunctional enzyme and sialylation during development. The need of UDP-GlcNAc 2-epimerase for a defined sialylation process is exemplified with the polysialylation of the neural cell adhesion molecule in embryonic stem cells.

Reduction of UDP-N-acetylglucosamine 2-Epimerase/N-Acetylmannosamine Kinase Activity and Sialylation in Distal Myopathy with Rimmed Vacuoles

“…ManNAc and NeuAc-Previous studies reported that hyposialylation in GNEϪ/Ϫ embryonic stem cells and GNE-defective cells can be repaired by feeding with the natural sialic acid precursor ManNAc (10,19). We examined the recovery of sialylation by the addition of NeuAc or ManNAc using primary cultured cells from patients and evaluated the sialylation status by lectin staining (Fig.…”

“…1) What is the status of sialylation activity in the patients with GNE mutations? One would expect sialylation to be impaired but not completely absent in DMRV/HIBM patients, because sialic acid is essential for embryonic development (10). In fact, homozygous null mutations have never been identified in patients (8,11).…”

An Oncogenic Protein Golgi Phosphoprotein 3 Up-regulates Cell Migration via Sialylation

“…Sialic acids also are believed to be essential for the early development of vertebrates (8). Enhanced expression of ␣2,6-linked sialylation on N-glycans often correlates with human cancer progression, metastatic spread, a poor prognosis, and stem cell markers (7,9,10).…”

Genetics of GNE myopathy in the non-Jewish Persian population

“…Only a few nonsense, frameshift, splice site variants, and indel variants 31,40 have been described in GNE, of which none was found in the homozygous state, 28 suggesting that this protein may have a critical role in embryonic development and viability, and that the total functional loss of GNE might be lethal in humans, as observed in mice. 14 At amino acid position 277 of GNE, two other variants have been reported: p.R277W and p.R277Q. The p.R277W variant was identified in families of European ancestry, 22,43,44 a family from China, 43 a family of Italian descent, 45 and a family from Japan).…”