The role of phosphorylated GSK3 isoforms in axonal regeneration of the central nerv-ous system

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Mature retinal ganglion cells (RGCs) normally fail to regenerate injured axons due to inhibitory molecules in the optic nerve myelin and glial scar as well as an insufficient intrinsic capability for regenerative growth. However, RGCs can be transformed into a regenerative state by cytokines, such as CNTF, or by genetic PTEN deletion. Preliminary data demonstrate that levels of phosphorylated GSK3 (pGSK3) markedly increase in mature RGCs upon optic nerve injury or PTEN deletion. Surprisingly, knockin mice expressing non-phosphorylatable, constitutively active GSK3 isoforms show significantly reduced RGC degeneration after optic nerve injury and in culture, CNTF-induced neurite growth of knockin RGCs is strongly in-creased compared to wild-type neurons. Here, we will test the hypotheses that GSK3 phos-phorylation functions as an intrinsic brake for axon regeneration and that sustained neuronal GSK3 activity facilitates axon regeneration after CNS injury. Furthermore, molecular mecha-nisms mediating these effects will be investigated.