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  • Review Article
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When sugars guide axons: insights from heparan sulphate proteoglycan mutants

Nature Reviews Genetics volume 5, pages 923–935 (2004)Cite this article

Key Points

  • Growing axons find their targets in the developing brain by sensing and integrating a large number of extracellular cues. Although several main families of ligands and their receptors are now known, it is clear that their signalling is modulated in complex ways. Heparan sulphate proteoglycans (HSPGs) are good candidates to be involved in this modulation.

  • HSPGs are a large class of molecules, comprising several proteins that are each post-translationally modified by the addition of one or more heparan-sulphate side chains. Extensive and variable modifications of the side chains lead to the extreme molecular diversity of HSPGs.

  • Previous biochemical evidence has shown that HSPGs can bind several known axon-guidance ligands, especially Slit. Functional experiments have shown that HSPGs are important for X. laevis retinal-axon guidance in vivo, and for Slit–Robo function in cultured neurons.

  • A set of recent genetic experiments in fly, worm, mouse and zebrafish have converged to show that HSPGs indeed have crucial roles in in vivo axon guidance.

  • Genetic interaction experiments show that HSPGs act with several known axon-guidance pathways, especially Kal-1 signalling and Slit–Robo signalling. Furthermore, analysis of heparan-sulphate modification mutants in Caenorhabditis elegans shows that specific modifications of heparan sulphate are important for particular axon-guidance decisions.

  • In the case of Slit–Robo signalling in the fly ventral nerve cord, the HSPG Syndecan has a role in controlling the distribution of Slit protein and probably binds directly to both Slit and Robo.

  • Future genetic analyses will help to elucidate the specific forms of HSPGs that are important for axon guidance; the mechanisms by which they act; and the other pathways with which they interact.

Abstract

Although there have previously been hints that heparan sulphate proteoglycans (HSPGs) are important for axon guidance, as they are for many other biological processes, there has been little in vivo evidence for interaction with known axon-guidance pathways. Genetic analyses of fly, mouse, nematode and zebrafish mutants now confirm the role of HSPGs in axon guidance and are beginning to show that they might have a key role in modulating the action of axon-guidance ligands and receptors.

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Figure 1: Three principal families of axon-guidance ligands and receptors that interact directly with heparan sulphate proteoglycans.
Figure 2: Synthesis of heparan-sulphate chains and known mutants in different model systems.
Figure 3: Models for guidance of axons by heparan sulphate proteoglycans.
Figure 4: Axon-guidance phenotypes of heparan sulphate proteoglycan mutants and genetic interactions with known guidance pathways.

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Acknowledgements

We thank the anonymous reviewers for their helpful suggestions and Scott Selleck for reading the manuscript. Work in our laboratory is supported by grants from the US National Science Foundation and National Institutes of Health to C.-B.C.

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Authors and Affiliations

  1. Department of Neurobiology and Anatomy, University of Utah School of Medicine, 20 North 1900 East, Salt Lake City, 84132, Utah, USA

    Jeong-Soo Lee & Chi-Bin Chien

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  1. Jeong-Soo Lee
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Correspondence to Chi-Bin Chien.

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FURTHER INFORMATION

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Glossary

GROWTH CONE

A specialized structure at the tip of a growing axon that senses guidance cues in the environment and steers the axon. Guidance receptors are often localized to the highly motile, actin-based filopodia and lamellipodia of the growth cone.

MIDLINE CROSSING

When axons cross the midline of the nervous system, passing from the left side to the right side, or vice versa. Midline crossing is one of the most fundamental, evolutionarily conserved axon-guidance decisions.

RETINAL GANGLION CELLS

The projection neurons that carry visual information from the eye to the brain.

CIRCUMFERENTIAL GUIDANCE

Guidance in a dorsal or ventral direction around the outside of the C. elegans body.

PIONEER AXONS

The earliest-growing axons in a nervous system that often help to guide later-growing axons.

COMMISSURAL AXONS

Axons that cross the midline and project to the other side of the nervous system.

OPTIC TECTUM

The primary brain target innervated by retinal axons in fish, frogs and chicks; homologous to the mammalian superior colliculus.

RETINOTECTAL TOPOGRAPHY

A map between the retina and tectum that preserves spatial information, which is crucial for visual processing.

SYNAPTIC PLASTICITY

Changes in synaptic strength — either increases or decreases — that are usually brought about in response to activity of a neuronal circuit. Plasticity is thought to be crucial for learning and memory.

EPIMERIZATION

An isomerization reaction that switches the position of two groups at a chiral carbon. For instance, C5-epimerization converts glucuronic acid to its diastereomer iduronic acid.

SULPHATION

Addition of a sulphate group to uronic acid residues (2-O-sulphation) or glucosamine residues (N-, 3- and 6-O-sulphation) of heparan-sulphate side chains.

HEREDITARY MULTIPLE EXOSTOSES

A dominant human disease in which bony spurs, or exostoses, develop at the end of long bones.

WING DISC

A sac-like primordial structure in a D. melanogaster embryo that gives rise to the adult wing.

LIPID RAFTS

Specialized cholesterol- and sphingolipid-rich microdomain structures in the cell membrane that are enriched in certain membrane proteins and are important for cellular signalling.

DENDRITIC SPINES

Mushroom-shaped structures on neuronal dendrites that receive synaptic input and bear postsynaptic densities. Changes in spine shape are thought to be important for modulating synaptic strength.

OLFACTORY BULB

Region in the rostral forebrain innervated by olfactory-receptor axons.

CRE

Cre is a site-specific recombinase that recognizes and binds to specific sites called loxP. Two loxP sites recombine at nearly 100% efficiency in the presence of Cre, allowing DNA cloned between two such sites to be removed by Cre-mediated recombination.

CEREBRAL CORTEX

The highly laminated gray matter of the cerebral hemisphere that mediates and integrates many higher-level brain functions.

FOREBRAIN COMMISSURES

Bundles of axons connecting the left and right halves of the forebrain, including the corpus callosum, hippocampal commissure and anterior commissure.

OPTIC CHIASM

An X-shaped structure in the ventral diencephalon where retinal axons from both eyes meet and partially cross. In mammals, most retinal axons project contralaterally at the chiasm, whereas a minority project ipsilaterally.

IPSILATERAL AXONS

Axons that do not cross the midline, instead projecting on the same side as the neuron's cell body.

LONGITUDINAL FASCICLES

Three bundles of axons that grow on each side of the fly nerve cord, parallel to the midline.

FASCICULATION

The aggregation of axons to form a bundle.

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Lee, JS., Chien, CB. When sugars guide axons: insights from heparan sulphate proteoglycan mutants. Nat Rev Genet 5, 923–935 (2004). https://doi.org/10.1038/nrg1490

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