Neurites regrowth of cortical neurons by GSK3beta inhibition independently of Nogo receptor 1.
Lesioned axons do not regenerate in the adult mammalian CNS, owing to the over-expression of inhibitory molecules such as myelin-derived proteins or chondroitin sulphate proteoglycans. In order to overcome axon inhibition, strategies based on extrinsic and intrinsic treatments have been developed. For myelin-associated inhibition, blockage with NEP1-40, receptor bodies or IN-1 antibodies has been used. In addition, endogenous blockage of cell signalling mechanisms induced by myelin-associated proteins is a potential tool for overcoming axon inhibitory signals. We examined the participation of glycogen synthase kinase 3beta (GSK3beta) and extracellular-related kinase (ERK) 1/2 in axon regeneration failure in lesioned cortical neurons. We also investigated whether pharmacological blockage of GSK3beta and ERK1/2 activities facilitates regeneration after myelin-directed inhibition in two models: (i) cerebellar granule cells and (ii) lesioned entorhino-hippocampal pathway in slice cultures, and whether the regenerative effects are mediated by Nogo Receptor 1 (NgR1). We demonstrate that, in contrast to ERK1/2 inhibition, the pharmacological treatment of GSK3beta inhibition strongly facilitated regrowth of cerebellar granule neurons over myelin independently of NgR1. Finally, these regenerative effects were corroborated in the lesioned entorhino-hippocampal pathway in NgR1-/- mutant mice. These results provide new findings for the development of new assays and strategies to enhance axon regeneration in injured cortical connections.
Seira
Oscar
O
Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia, Barcelona, Spain.
Gavín
Rosalina
R
Gil
Vanessa
V
Llorens
Franc
F
Rangel
Alejandra
A
Soriano
Eduardo
E
del Río
José Antonio
JA
D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D019771:Axotomy / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D018920:Coculture Techniques / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009185:Myelin Proteins / Q000378:metabolism / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D011247:Pregnancy; D051381:Rats; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide / Q000172:deficiency; D013997:Time Factors; D053675:Versicans / Q000378:metabolism
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D007211:Indoles; D008301:Maleimides; D009185:Myelin Proteins; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; C000603199:RTN4 protein, human; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat; C486581:Rtn4r protein, rat; C417521:SB 216763; C508324:Vcan protein, rat; D053675:Versicans; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; C013411:biocytin; D008239:Lysine