Glycosylation in Axonal Guidance

Abstract

How millions of axons navigate accurately toward synaptic targets during development is a long-standing question. Over decades, multiple studies have enriched our understanding of axonal pathfinding with discoveries of guidance molecules and morphogens, their receptors, and downstream signalling mechanisms. Interestingly, classification of attractive and repulsive cues can be fluid, as single guidance cues can act as both. Similarly, guidance cues can be secreted, chemotactic cues or anchored, adhesive cues. How a limited set of guidance cues generate the diversity of axonal guidance responses is not completely understood. Differential expression and surface localization of receptors, as well as crosstalk and spatiotemporal patterning of guidance cues, are extensively studied mechanisms that diversify axon guidance pathways. Posttranslational modification is a common, yet understudied mechanism of diversifying protein functions. Many proteins in axonal guidance pathways are glycoproteins and how glycosylation modulates their function to regulate axonal motility and guidance is an emerging field. In this review, we discuss major classes of glycosylation and their functions in axonal pathfinding. The glycosylation of guidance cues and guidance receptors and their functional implications in axonal outgrowth and pathfinding are discussed. New insights into current challenges and future perspectives of glycosylation pathways in neuronal development are discussed.

Regio-Specific N-Glycome and N-Glycoproteome Map of the Elderly Human Brain With and Without Alzheimer’s Disease

“…As the N-glycans were enriched from proteins on the cell membrane, the loss of these species, specifically the sialic acid moieties, may mean the loss of intracellular interactions on the cell surface of the brain cells. Studies involving neural cell adhesion molecules (NCAMs) showed that changes in glycosylation were associated with the disruption of several NCAM-dependent neurodevelopmental processes ( 44 ). A large body of work on brain sialylation has focused primarily on polysialic acid ( 34 , 39 , 45 , 46 ); however, the large abundances of sialofucosylated species should encourage the examination of sialofucosylated NCAMs in axonal guidance.…”

A novel cytoskeletal action of xylosides

“…In terms of axon guidance, many studies have shown the bifunctionality of HS and CS as guidance cues. HS is commonly associated with permissive substrates while CS, especially 4-sulfated CS, is seen as inhibitory [40]. These actions clearly depend upon alterations in the cytoskeleton.…”

A Novel Cytoskeletal Action of Xylosides

“…In terms of axon guidance, many studies have shown the bifunctionality of HS and CS as guidance cues. HS is commonly associated with permissive substrates while CS, especially 4-sulfated CS, is seen as inhibitory (36). Proteins that have been implicated in axon guidance such as Sema5A and RPTPσ have been shown to interact with both CS and HS at binding sites unique to the type of GAG chain (7, 37).…”