Neural circuits are formed with great precision during development. Accumulated evidence over the past three decades has demonstrated that growing axons are navigated toward their targets by the combined actions of attractants and repellents together with their receptors. It has long been known that proteoglycans, glycosylated proteins possessing covalently attached glycosaminoglycans, play a critical role in axon guidance; however, the molecular mechanisms by which proteoglycans regulate axon behaviors remain largely unknown. Glycosaminoglycans such as heparan sulfate and chondroitin sulfate are large linear polysaccharides composed of repeating disaccharide units that are highly modified by specific sulfation and epimerization. Recent biochemical and molecular biological studies have identified the enzymes that are involved in the biosynthesis of glycosaminoglycans. Interestingly, many mutants lacking glycosaminoglycan‐synthesizing enzymes or proteoglycans in several model organisms show defects in specific nerve tract formation. In parallel, detailed biochemical studies have identified the molecular interactions between axon guidance molecules and glycosaminoglycans that have specific modification in their sugar chains. This review summarizes the structure and function of axon guidance molecules and glycosaminoglycans, and then tries to combine the knowledge from these studies to understand the role of proteoglycans from a new vantage point. Deciphering the sugar code is important for understanding the complicated nature of proteoglycans in axon guidance.

Neural circuits are formed by the combined actions of axon guidance molecules. Proteoglycans play critical roles in regulating axon guidance through the interaction between signaling molecules and glycosaminoglycan chains attached to the core protein. This paper summarizes the structure and functions of axon guidance molecules and glycosaminoglycans and reviews the molecular mechanisms by which proteoglycans regulate axon guidance from a new vantage point.

This article is part of the 60th Anniversary special issue.