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

成熟的视网膜神经节细胞（RGC）通常由于视神经髓鞘和胶质瘢痕中的抑制分子以及再生生长的内在能力不足而不能再生受损的轴突。然而，RGCs可以通过细胞因子如CNTF或通过基因PTEN缺失转化为再生状态。初步数据表明，磷酸化的GSK 3（pGSK 3）的水平显着增加视神经损伤或PTEN缺失后，在成熟的RGCs。令人惊讶的是，敲入小鼠表达非磷酸化的，组成型活性的GSK 3亚型显示出显着减少RGC变性视神经损伤后，在培养中，CNTF诱导的神经突起生长敲入RGC是强烈增加相比，野生型神经元。在这里，我们将测试的假设，即GSK 3 β-磷酸化功能作为一个内在的制动轴突再生和持续的神经元GSK 3活性促进轴突再生后中枢神经系统损伤。此外，介导这些影响的分子机制将被调查。

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.