title: Histone acetylation inhibitors promote axon growth in adult dorsal root ganglia neurons.
abstract: Intrinsic mechanisms that guide damaged axons to regenerate following spinal cord injury remain poorly understood. Manipulation of posttranslational modifications of key proteins in mature neurons could reinvigorate growth machinery after injury. One such modification is acetylation, a reversible process controlled by two enzyme families, the histone deacetylases (HDACs) and the histone acetyl transferases (HATs), acting in opposition. Whereas acetylated histones in the nucleus are associated with upregulation of growth-promoting genes, deacetylated tubulin in the axoplasm is associated with more labile microtubules, conducive to axon growth. This study investigates the effects of HAT and HDAC inhibitors on cultured adult dorsal root ganglia (DRG) neurons and shows that inhibition of HATs by anacardic acid or CPTH2 improves axon outgrowth, whereas inhibition of HDACs by TSA or tubacin inhibits axon growth. Anacardic acid increased the number of axons able to cross an inhibitory chondroitin sulfate proteoglycan border. Histone acetylation but not tubulin acetylation level was affected by HAT inhibitors, whereas tubulin acetylation levels were increased in the presence of the HDAC inhibitor tubacin. Although the microtubule-stabilizing drug taxol did not have an effect on the lengths of DRG axons, nocodazole decreased axon lengths. Determining the mechanistic basis will require future studies, but this study shows that inhibitors of HAT can augment axon growth in adult DRG neurons, with the potential of aiding axon growth over inhibitory substrates produced by the glial scar.
authors.affiliation: Department of Neuroscience, Shriners Hospitals for Pediatric Research Center, Temple University, Philadelphia, Pennsylvania.
authors.forename: Shen
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, Shriners Hospitals for Pediatric Research Center, Temple University, Philadelphia, Pennsylvania.
authors.forename: Kutaiba
authors.initials: K
authors.lastname: Nazif
authors.affiliation: Department of Neuroscience, Shriners Hospitals for Pediatric Research Center, Temple University, Philadelphia, Pennsylvania.
authors.forename: Alexander
authors.initials: A
authors.lastname: Smith
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Baas
authors.affiliation: Department of Neuroscience, Shriners Hospitals for Pediatric Research Center, Temple University, Philadelphia, Pennsylvania.
authors.forename: George M
authors.initials: GM
authors.lastname: Smith
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000201:enzymology*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000813:Anilides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C474316:tubacin; D051548:Histone Acetyltransferases
keywords: CSPG; DRG; HAT; HDAC; acetylation; axon; histone; microfluidic; microtubule; neuron