Chondroitin-4-sulfation negatively regulates axonal guidance and growth

J Cell Sci, 2008 · DOI: 10.1242/jcs.032649 · Published: September 15, 2008

Simple Explanation

Glycosaminoglycans (GAGs) are important in cell signaling and structure. This study focuses on chondroitin sulfate (CS), a type of GAG, and how specific modifications, especially sulfation, affect nerve cell growth and direction. The researchers found that a specific type of CS, chondroitin-4-sulfate (CS-A), strongly repels growing nerve fibers. Manipulating the sulfation of CS chains changes their ability to guide axons. After spinal cord injuries in mice, there's a rapid increase in 4-sulfated CS in areas that don't support nerve regeneration. This suggests that specific sulfation patterns act as instructions to control nerve cell behavior.

Study Duration

Not specified

Participants

Cultured primary neurons, mouse cerebellar granule neurons, embryonic mouse cortical neurons, primary cultures of cerebral cortical astrocytes, adult mice

Evidence Level

Not specified

Key Findings

1
Chondroitin-4-sulfate (CS-A), but not chondroitin-6-sulfate (CS-C), exhibits a strong negative guidance cue to mouse cerebellar granule neurons, indicating that sulfation at the C4 position of the GalNAc moiety presents a specific negative guidance cue to axons.
2
Reactive astrocytes produce more 4-sulfated CS GAG chains, and knockdown of C4ST1 reduces the level of 4-sulfation in CS GAG chains, resulting in a less inhibitory ECM, demonstrating the essential roles of C4ST1 and 4-sulfated CS GAG chains in the induction of repellent activity of astrocytes by TGFβ1 treatment.
3
4-sulfated CS GAG chains are acutely upregulated and deposited by reactive astrocytes in an animal model of spinal cord injury, which confirms a specific upregulation and deposition of 4-sulfated GAG by reactive astrocytes after CNS injury.

Research Summary

This study demonstrates that specific sulfation in chondroitin sulfate (CS) glycosaminoglycan (GAG) chains mediates neuronal guidance cues and axonal growth inhibition, with chondroitin-4-sulfate (CS-A) acting as a strong negative guidance cue to mouse cerebellar granule neurons. The researchers found that 4-sulfated CS GAG chains are rapidly and significantly increased in regions that do not support axonal regeneration proximal to spinal cord lesions in mice, suggesting that this specific sulfation regulates neuronal function. By using enzymatic and gene-based manipulations of 4-sulfation, the study provides evidence that small changes in 4-sulfation of CS GAG chains have major effects on the potency of CSPGs to impart guidance cues to neurons.

Practical Implications

Therapeutic Potential

Modulation of sulfation in CSPGs serves as a signal to restrict axonal regrowth and may be an important new therapeutic direction for regenerative biomedicine.

Understanding Axonal Guidance

The discovery that CS-A, but not CS-C, repels axons highlights the structural specificity for signaling by the sulfated disaccharides that comprise CS chains, enhancing the understanding of axonal guidance mechanisms.

Targeting Reactive Astrocytes

Since reactive astrocytes in the injured brain are detrimental to neuronal regeneration due to increased production of sulfated proteoglycans, modulating the sulfation in astrocytic CSPGs could change the interaction between astrocytes and neurons.

Study Limitations

1
The study focuses primarily on in vitro experiments and an animal model, which may not fully represent the complexity of human CNS regeneration.
2
The precise mechanisms by which 4-sulfation of CS GAG chains alters axonal direction and limits the rate of axonal extension are not fully elucidated.
3
The potential roles of other sulfation patterns and other GAG chain modifications in axonal regeneration are not fully explored.

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