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

磷酸化 GSK3 亚型在中枢神经系统轴突再生中的作用

• 批准号: 249541465
• 负责人: Professor Dr. Dietmar Fischer
• 金额: --
• 依托单位: Zentrum für Pharmakologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/249541465?language=en
• 关键词: role; phosphorylated; GSK3; isoforms; axonal

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.

成熟的视网膜神经节细胞（RGCs）通常由于视神经髓鞘和胶质瘢痕中的抑制分子以及内在再生生长能力不足而无法再生受损的轴突。然而，RGCs可以通过细胞因子（如CNTF）或基因PTEN缺失转化为再生状态。初步数据表明，视神经损伤或PTEN缺失后，成熟RGCs中磷酸化的GSK3 （pGSK3）水平显著增加。令人惊讶的是，表达非磷酸化的、组成活性的GSK3亚型的敲入小鼠在视神经损伤后显示出显著减少的RGC变性，并且在培养中，与野生型神经元相比，cntf诱导的敲入RGC的神经突生长明显增加。在这里，我们将验证GSK3磷酸化作为轴突再生的内在抑制的假设，以及持续的神经元GSK3活性促进中枢神经系统损伤后轴突再生的假设。此外，还将研究介导这些效应的分子机制。

项目成果

Boosting CNS axon regeneration by harnessing antagonistic effects of GSK3 activity

• DOI: 10.1073/pnas.1621225114
• 发表时间: 2017-07-03
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Leibinger, Marco;Andreadaki, Anastasia;Fischer, Dietmar
• 通讯作者: Fischer, Dietmar

Promotion of Functional Nerve Regeneration by Inhibition of Microtubule Detyrosination

• DOI: 10.1523/jneurosci.4486-15.2016
• 发表时间: 2016-04-06
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Gobrecht, Philipp;Andreadaki, Anastasia;Fischer, Dietmar
• 通讯作者: Fischer, Dietmar

GSK3-CRMP2 signaling mediates axonal regeneration induced by Pten knockout

• DOI: 10.1038/s42003-019-0524-1
• 发表时间: 2019-08-23
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Leibinger, Marco;Hilla, Alexander M.;Fischer, Dietmar
• 通讯作者: Fischer, Dietmar