Key Points
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Glycans (chains of monosaccharides) are becoming increasingly recognized as participants in neural cell interactions in the developing and adult nervous system. They are involved in diverse functions that depend on cell recognition, such as cell migration, neurite outgrowth and fasciculation, synapse formation and stabilization, and modulation of synaptic efficacy.
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The addition of monosaccharides in different configurations to ceramide leads to the formation of various glycolipids. Glycoproteins, proteoglycans and mucins carry glycans that are covalently attached to protein backbones in various linkages. There are two broad groups of glycoproteins — N-glycans and O-glycans — which differ in their nature of the linkage to the protein backbone.
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Polysialic acid is carried by the neural cell adhesion molecule NCAM. It decreases homophilic NCAM-mediated interactions and is an important ingredient in NCAM's functions: for instance, it enhances migration of neural stem cells, promotes neurite outgrowth and is involved in regenerative processes after trauma and synaptic plasticity during learning and memory.
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Oligomannosides are usually transient biosynthetic appendices of N-linked carbohydrates on glycoproteins en route to the cell surface and the extracellular matrix. In most tissues, oligomannosides are eliminated during the processing of sugars to yield mature N-glycans, but predominantly in the brain, they are carried to the cell surface on recognition molecules.
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In the nervous system, myelin-associated glycoprotein (MAG) was the first molecule that was shown to bind α2,3-linked sialic acid. MAG is involved not only in myelin formation, but also in myelin maintenance. It has received particular attention because it enhances in vitro neurite outgrowth at early developmental stages, but inhibits neurite outgrowth in the adult.
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The human natural killer cell glycan HNK1 is found on glycolipids and glycoproteins, and it is the target epitope for auto-antibodies in severe peripheral neuropathies. Several receptors for HNK1 with roles in development have been identified in the nervous system, and HNK1 has also been implicated in synaptic plasticity and motor neuron regeneration.
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Glycosaminoglycans are long repeating linear polymers of disaccharides. The main glycosaminoglycans in the brain are chondroitin sulphates and heparan sulphates, which are carried by different protein backbones. Chondroitin sulphate proteoglycans and hyaluronan (a large polymer consisting of alternating glucuronic acid and N-acetylglucosamine residues) are localized in perineuronal nets, which are believed to be crucial for regulating synaptic efficacy.
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Chondroitin sulphate is a repellent for growth cones, acting as a molecular barrier, particularly in choice situations. Removal of chondroitin sulphate chains from proteoglycans reduces their barrier functions and allows regrowth of severed axons and synaptic rearrangements.
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Glycans have been shown to have pivotal roles in nervous system development, regeneration and synaptic plasticity. Owing to their structural richness, they could be as versatile as the protein backbone that carries them.
Abstract
Carbohydrate-carrying molecules in the nervous system have important roles during development, regeneration and synaptic plasticity. Carbohydrates mediate interactions between recognition molecules, thereby contributing to the formation of a complex molecular meshwork at the cell surface and in the extracellular matrix. The tremendous structural diversity of glycan chains allows for immense combinatorial possibilities that might underlie the fine-tuning of cell–cell and cell–matrix interactions.
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The authors are grateful to A. Dityatev for his comments on the manuscript and the Deutsche Forschungsgemeinschaft for support.
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DATABASES
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Glossary
- GLYCOSIDIC BONDS
-
Covalent bonds that are formed between two monosaccharide molecules by means of a dehydration reaction. The linkage terminology is based on which carbon atoms in the two sugars are linked and the position of the linking oxygen group. For example, if carbon-1 (C-1) of sugar-1 is linked to C-4 of sugar-2, and the linking oxygen is below the plane of the sugar-1 ring, the linkage is referred to as an α1,4 glycosidic bond. If the oxygen had been above the plane of the ring, the linkage would be designated β1,4.
- MUCIN
-
A highly glycosylated protein that is rich in serine and/or threonine O-glycosylation.
- ROSTRAL MIGRATORY STREAM
-
Neuroblasts from the subventricular zone migrate in the rostral migratory stream (RMS) towards the olfactory bulb in a so-called tangential migration and move from the rostral tip of the migratory stream by detaching from each other to initiate radial migration to their target areas in the olfactory bulb.
- MOSSY FIBRES
-
Axons of dentate gyrus granule cells, which constitute the main excitatory input to CA3 pyramidal cells in the hippocampus.
- PERFORATED SYNAPSES
-
Synapses in which the postsynaptic density is discontinuous.
- VOLUME TRANSMISSION
-
A mechanism of extrasynaptic intercellular communication that relies on signal diffusion through the extracellular fluid.
- RECOGNITION MOLECULE
-
Recognition molecules belong to diverse sets of families, such as the immunoglobulin superfamily, the integrin family, the receptor tyrosine kinase families, and epidermal growth factor repeats-containing family of molecules. Glycolipids and proteoglycans are also recognition molecules. As carbohydrate-carrying proteins, they can be either transmembrane molecules, glycosylphosphatidyl inositol anchored to the cell surface or extracellular matrix molecules that fill the space between cells.
- EPITOPE
-
Part of a molecule that is recognized by an antibody. It consists of several monosaccharides and/or amino acids, and in the case of a glycan it can be exposed in a distinct three-dimensional configuration, often in particular arrangements with amino acids.
- HIGH-MOBILITY GROUP PROTEINS
-
Non-histone proteins that are involved in chromatin structure and gene regulation.
- PEPTIDOMIMETICS
-
Peptidomimetics are peptides that mimic other molecules, for example, carbohydrates, in their ability to bind to other molecules. In terms of three-dimensional structure, they are similar to the compounds that they mimic.
- STEP-DOWN PASSIVE AVOIDANCE TASK
-
A behavioural experiment, in which an animal learns to associate stepping down from a raised platform with an aversive stimulus, such as electric shock. The name of the task derives from the fact that the animal learns to passively stay on the platform to avoid the stimulus.
- INWARDLY RECTIFYING K+ CHANNELS
-
Potassium channels that allow long depolarizing responses, as they close during depolarizing pulses and open with steep voltage dependence on hyperpolarization. They are called inward rectifiers because current flows through them more easily into than out of the cell.
- PERINEURONAL NETS
-
Agglomerates of extracellular matrix components, including molecules of the lectican family of chondroitin sulphate proteoglycans, such as aggrecan, versican, brevican and neurocan, as well as hyaluronan and tenascin-R or tenascin-C. These accumulations are found around cell bodies and dendrites of certain classes of neurons, mainly parvalbumin-positive inhibitory interneurons. The function of these nets is unknown, but probably relates to the regulation of synaptic plasticity.
- AMBLYOPIC
-
Amblyopia is an eye problem that causes poor vision. It is also known as 'lazy eye', and is often associated with squint.
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Kleene, R., Schachner, M. Glycans and neural cell interactions. Nat Rev Neurosci 5, 195–208 (2004). https://doi.org/10.1038/nrn1349
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DOI: https://doi.org/10.1038/nrn1349
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