Neurites regrowth of cortical neurons by GSK3β inhibition independently of Nogo Receptor 1

Oscar Seira, Rosalina Gavin, Vanessa Gil, Franc Llorens, Alejandra Rangel, Eduardo Soriano, Jose Antonio Del Rio

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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 3β (GSK3β) and extracellular-related kinase (ERK) 1/2 in axon regeneration failure in lesioned cortical neurons. We also investigated whether pharmacological blockage of GSK3β and ERK1/2 activities facilitates regeneration after myelin-directed inhibition in two models: (i) cerebellar granule cells and (ii) lesioned entorhinohippocampal 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 GSK3β 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.
    Original languageEnglish
    Pages (from-to)1644-1658
    Number of pages15
    JournalJournal of Neurochemistry
    Volume113
    Issue number6
    DOIs
    Publication statusPublished - 2010

    Keywords

    • axons
    • mammals
    • neurons

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