Intra-axonal translation of RhoA promotes axon growth inhibition by CSPG.
Chondroitin sulfate proteoglycans (CSPGs) are a major component of the glial scar that contributes to the limited regeneration of the CNS after axonal injury. However, the intracellular mechanisms that mediate the effects of CSPGs are not fully understood. Here we show that axonal growth inhibition mediated by CSPGs requires intra-axonal protein synthesis. Application of CSPGs to postnatal rat dorsal root ganglia axons results in an increase in the axonal levels of phosphorylated 4E-BP1, a marker of increased protein translation. Axons grown in media containing CSPGs exhibit markedly reduced growth rates, which can be restored by the selective application of protein synthesis inhibitors to distal axons. We show that these axons contain transcripts encoding RhoA, a regulator of the cytoskeleton that is commonly used by the signaling pathways activated by many inhibitors of axon growth. We also show that selective application of CSPGs to axons results in increased intra-axonal synthesis of RhoA and that depletion of RhoA transcripts from axons results in enhanced growth of axons in the presence of CSPGs. These data identify local translation as an effector pathway of CSPGs and demonstrate that local translation of RhoA contributes to the axon growth inhibitory effect of CSPGs.
Department of Pharmacology, Weill Medical College, Cornell University, New York, New York 10065, USA.
Breset A
BA
Walker
Sheng-Jian
SJ
Ji
Samie R
SR
Jaffrey
D000818:Animals; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000502:physiology*; D005260:Female; D005727:Ganglia, Spinal / Q000254:growth & development / Q000378:metabolism; D006131:Growth Inhibitors / Q000502:physiology*; D008297:Male; D014176:Protein Biosynthesis / Q000235:genetics*; D051381:Rats; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics*
D011508:Chondroitin Sulfate Proteoglycans; D006131:Growth Inhibitors; D020742:rhoA GTP-Binding Protein