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The Journal of Neuroscience, December 26, 2007, 27(52):14494-14501; doi:10.1523/JNEUROSCI.2807-07.2007

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Development/Plasticity/Repair
Inhibiting Glycosaminoglycan Chain Polymerization Decreases the Inhibitory Activity of Astrocyte-Derived Chondroitin Sulfate Proteoglycans

Tracy L. Laabs,^1,2 Hang Wang,¹ Yasuhiro Katagiri,¹ Thomas McCann,¹ James W. Fawcett,² and Herbert M. Geller¹

¹Developmental Neurobiology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, and ²Cambridge University Centre for Brain Repair, Cambridge CB2 2PY, United Kingdom

Correspondence should be addressed to Dr. Herbert M. Geller, Developmental Neurobiology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, MSC 1754, Bethesda, MD 20892-1754. Email: geller{at}helix.nih.gov

Chondroitin sulfate proteoglycans (CSPGs) are upregulated in the CNS after injury and participate in the inhibition of axon regeneration mainly through their glycosaminoglycan (GAG) side chains. In the present study, we have identified a new way to alleviate the inhibition of axonal regeneration by CSPG GAGs. We have successfully decreased the amount of CSPG GAG produced by astrocytes by targeting chondroitin polymerizing factor (ChPF), a key enzyme in the CSPG biosynthetic pathway. Using short interfering RNA (siRNA), we reduced ChPF mRNA levels by 70% in both the Neu7 astrocyte cell line and primary rat astrocytes. This reduction leads to a decrease in ChPF protein levels and a reduced amount of CSPG GAG chains in the conditioned media (CM) of these cells. Secretion of neurocan by primary astrocytes and NG2 core protein by Neu7 cells transfected with ChPF siRNA is not decreased, suggesting that inhibiting GAG chain synthesis does not affect core protein trafficking from these cells. CM from siRNA-treated Neu7 cells is a less repulsive substrate for axons than CM from control cells. In addition, axonal outgrowth from cerebellar granule neurons is increased on or in CM from ChPF siRNA-treated Neu7 cells. These data indicate that targeting the biosynthesis of CSPG GAG is a potentially new therapeutic avenue for decreasing CSPG GAG produced by astrocytes after CNS injury.

Key words: axon guidance; granule neuron; siRNA; chondroitin polymerizing factor; Neu7 cells; matrix

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Received Dec. 21, 2006; revised Nov. 14, 2007; accepted Nov. 21, 2007.

Correspondence should be addressed to Dr. Herbert M. Geller, Developmental Neurobiology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, MSC 1754, Bethesda, MD 20892-1754. Email: geller{at}helix.nih.gov

Related articles in J. Neurosci.:

Knocking Down Glycosaminoglycan Synthesis

Jennifer W. J. Wong
J. Neurosci. 2008 28: 2688-2689. [Full Text]  

This article has been cited by other articles:

				J. W. J. Wong Knocking Down Glycosaminoglycan Synthesis J. Neurosci., March 12, 2008; 28(11): 2688 - 2689. [Full Text] [PDF]

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