The monosialoganglioside GM1a protects against complement attack.

The complement system is a part of the innate immune system in the fluid phase and efficiently eliminates pathogens. However, its activation requires tight regulation on the host cell surface in order not to compromise cellular viability. Previously, we showed that loss of placental cell surface sialylation in mice in vivo leads to a maternal complement attack at the fetal-maternal interface, ultimately resulting in loss of pregnancy.

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

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.

The Loss of Polysialic Acid Impairs the Contractile Phenotype of Peritubular Smooth Muscle Cells in the Postnatal Testis.

In the testis, the germinal epithelium of seminiferous tubules is surrounded by contractile peritubular cells, which are involved in sperm transport. Interestingly, in postnatal testis, polysialic acid (polySia), which is also an essential player for the development of the brain, was observed around the tubules. Western blotting revealed a massive decrease of polySia from postnatal day 1 towards puberty, together with a fundamental reduction of the net-like intertubular polySia.

Podocyte-Specific Sialylation-Deficient Mice Serve as a Model for Human FSGS.

Background: The etiology of steroid-resistant nephrotic syndrome, which manifests as FSGS, is not completely understood. Aberrant glycosylation is an often underestimated factor for pathologic processes, and structural changes in the glomerular endothelial glycocalyx have been correlated with models of nephrotic syndrome. Glycans are frequently capped by sialic acid (Sia), and sialylation's crucial role for kidney function is well known.

Sialic acid is a critical fetal defense against maternal complement attack.

The negatively charged sugar sialic acid (Sia) occupies the outermost position in the bulk of cell surface glycans. Lack of sialylated glycans due to genetic ablation of the Sia-activating enzyme CMP-sialic acid synthase (CMAS) resulted in embryonic lethality around day 9.5 post coitum (E9.

Sialylation Is Dispensable for Early Murine Embryonic Development in Vitro.

The negatively charged nonulose sialic acid (Sia) is essential for murine development in vivo. In order to elucidate the impact of sialylation on differentiation processes in the absence of maternal influences, we generated mouse embryonic stem cell (mESC) lines that lack CMP-Sia synthetase (CMAS) and thereby the ability to activate Sia to CMP-Sia. Loss of CMAS activity resulted in an asialo cell surface accompanied by an increase in glycoconjugates with terminal galactosyl and oligo-LacNAc residues, as well as intracellular accumulation of free Sia.

A crucial role for polysialic acid in developmental interneuron migration and the establishment of interneuron densities in the mouse prefrontal cortex.

Polysialic acid (polySia) is a unique glycan modification of the neural cell adhesion molecule NCAM and a major determinant of brain development. Polysialylation of NCAM is implemented by the two polysialyltransferases (polySTs) ST8SIA2 and ST8SIA4. Dysregulation of the polySia-NCAM system and variation in ST8SIA2 has been linked to schizophrenia and other psychiatric disorders.

Polysialic acid/neural cell adhesion molecule modulates the formation of ductular reactions in liver injury.

Unlabelled: In severe liver injury, ductular reactions (DRs) containing bipotential hepatic progenitor cells (HPCs) branch from the portal tract. Neural cell adhesion molecule (NCAM) marks bile ducts and DRs, but not mature hepatocytes. NCAM mediates interactions between cells and surrounding matrix; however, its role in liver development and regeneration is undefined.

Laser microdissection of paraffin embedded tissue as a tool to estimate the sialylation status of selected cell populations.

In vertebrates, sialic acids occur at the terminal end of glycans mediating numerous biological processes like cell differentiation or tumor metastasis. Consequently, the cellular sialylation status under healthy and pathological conditions is of high interest. Existing analytical strategies to determine sialylation patterns are mostly applied to tissue samples consisting of a mixture of different cell types.

CMP-Sialic Acid Synthetase: The Point of Constriction in the Sialylation Pathway.

Sialoglycoconjugates form the outermost layer of animal cells and play a crucial role in cellular communication processes. An essential step in the biosynthesis of sialylated glycoconjugates is the activation of sialic acid to the monophosphate diester CMP-sialic acid. Only the activated sugar is transported into the Golgi apparatus and serves as a substrate for the linkage-specific sialyltransferases.

Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice.

Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is crucial for nervous system development and brain plasticity. PolySia attachment is catalyzed by the polysialyltransferases (polySTs) ST8SIA2 and ST8SIA4, two enzymes with distinct but also common functions during neurodevelopment and in the adult brain. A growing body of evidence links aberrant levels of NCAM and polySia as well as variation in the ST8SIA2 gene to neuropsychiatric disorders, including schizophrenia.

Deficits in sialylation impair podocyte maturation.

The role of sialylation in kidney biology is not fully understood. The synthesis of sialoglycoconjugates, which form the outermost structures of animal cells, requires CMP-sialic acid, which is a product of the nuclear enzyme CMAS. We used a knock-in strategy to create a mouse with point mutations in the canonical nuclear localization signal of CMAS, which relocated the enzyme to the cytoplasm of transfected cells without affecting its activity.

Identification and biochemical characterization of two functional CMP-sialic acid synthetases in Danio rerio.

Sialic acids (Sia) form the nonreducing end of the bulk of cell surface-expressed glycoconjugates. They are, therefore, major elements in intercellular communication processes. The addition of Sia to glycoconjugates requires metabolic activation to CMP-Sia, catalyzed by CMP-Sia synthetase (CMAS).

Homeostatic regulation of NCAM polysialylation is critical for correct synaptic targeting.

During development, axonal projections have a remarkable ability to innervate correct dendritic subcompartments of their target neurons and to form regular neuronal circuits. Altered axonal targeting with formation of synapses on inappropriate neurons may result in neurodevelopmental sequelae, leading to psychiatric disorders. Here we show that altering the expression level of the polysialic acid moiety, which is a developmentally regulated, posttranslational modification of the neural cell adhesion molecule NCAM, critically affects correct circuit formation.

Thalamocortical pathfinding defects precede degeneration of the reticular thalamic nucleus in polysialic acid-deficient mice.

The modification of the neural cell adhesion molecule (NCAM) with polysialic acid (polySia) is tightly linked to neural development. Genetic ablation of the polySia-synthesizing enzymes ST8SiaII and ST8SiaIV generates polySia-negative but NCAM-positive (II(-/-)IV(-/-)) mice characterized by severe defects of major brain axon tracts, including internal capsule hypoplasia. Here, we demonstrate that misguidance of thalamocortical fibers and deficiencies of corticothalamic connections contribute to internal capsule defects in II(-/-)IV(-/-) mice.

Synaptic cell adhesion molecule SynCAM 1 is a target for polysialylation in postnatal mouse brain.

Among the large set of cell surface glycan structures, the carbohydrate polymer polysialic acid (polySia) plays an important role in vertebrate brain development and synaptic plasticity. The main carrier of polySia in the nervous system is the neural cell adhesion molecule NCAM. As polySia with chain lengths of more than 40 sialic acid residues was still observed in brain of newborn Ncam(-/-) mice, we performed a glycoproteomics approach to identify the underlying protein scaffolds.

Quantification of nucleotide-activated sialic acids by a combination of reduction and fluorescent labeling.

Sialic acids usually represent the terminal monosaccharide of glycoconjugates and are directly involved in many biological processes. The cellular concentration of their nucleotide-activated form is one pacemaker for the highly variable sialylation of glycoconjugates. Hence, the determination of CMP-sialic acid levels is an important factor to understand the complex glycosylation machinery of cells and to standardize the production of glycotherapeutics.

Polysialic acid affects pathophysiological consequences of status epilepticus.

Modulation of the neural cell adhesion molecule by the attachment of polysialic acid residues through the polysialyl-transferase, ST8SiaIV, regulates neuronal plasticity and affects cellular alterations in the epileptic brain. Here, we determined the impact of ST8SiaIV deficiency on the pathophysiological consequences of status epilepticus (SE). ST8SiaIV deficiency reduced the latency to SE induction and increased SE-mediated mortality.

A C-terminal phosphatase module conserved in vertebrate CMP-sialic acid synthetases provides a tetramerization interface for the physiologically active enzyme.

The biosynthesis of sialic acid-containing glycoconjugates is crucial for the development of vertebrate life. Cytidine monophosphate-sialic acid synthetase (CSS) catalyzes the metabolic activation of sialic acids. In vertebrates, the enzyme is chimeric, with the N-terminal domain harboring the synthetase activity.

NCAM and polysialyltransferase profiles match dopaminergic marker gene expression but polysialic acid is dispensable for development of the midbrain dopamine system.

The modification of the neural cell adhesion molecule (NCAM) with polysialic acid plays a pivotal role in the developing nervous system. Here we studied the expression and function of polysialic acid during development of the mesencephalic dopaminergic system of mice. Using immunohistochemistry, polysialic acid was detected on nestin-positive radial glia processes and on cell somata in the pial zone of the midbrain at embryonic day E11.

Polysialic acid governs T-cell development by regulating progenitor access to the thymus.

Although the polysialyltransferase ST8Sia IV is expressed in both primary and secondary human lymphoid organs, its product, polysialic acid (polySia), has been largely overlooked by immunologists. In contrast, polySia expression and function in the nervous system has been well characterized. In this context, polySia modulates cellular adhesion, migration, cytokine response, and contact-dependent differentiation.

Imbalance of neural cell adhesion molecule and polysialyltransferase alleles causes defective brain connectivity.

The neural cell adhesion molecule (NCAM) and its post-translational modification polysialic acid (polySia) are broadly implicated in neural development. Mice lacking the polysialyltransferases ST8SiaII and ST8SiaIV are devoid of polySia, and show severe malformation of major brain axon tracts. Here, we demonstrate how allelic variation of three interacting gene products (NCAM, ST8SiaII and ST8SiaIV) translates into various degrees of anterior commissure, corpus callosum and internal capsule hypoplasia.

Brain development needs sugar: the role of polysialic acid in controlling NCAM functions.

Polysialic acid (polySia) is a major regulator of cell-cell interactions in the developing nervous system and a key factor in maintaining neural plasticity. As a polyanionic molecule with high water binding capacity, polySia increases the intercellular space and creates conditions that are permissive for cellular plasticity. While the prevailing model highlights polySia as a non-specific regulator of cell-cell contacts, this review concentrates on recent studies in knockout mice indicating that a crucial function of polySia resides in controlling interactions mediated by its predominant protein carrier, the neural cell adhesion molecule NCAM.

Level and localization of polysialic acid is critical for early peripheral nerve regeneration.

PolySia, the most striking post-translational modification of the neural cell adhesion molecule, is down-regulated during postnatal development. After peripheral nerve lesion, polySia is located on neuronal and glial cells normally not synthesizing polySia. However, structural consequences of reduced polySia content for peripheral nerve regeneration have not yet been clear.