Department of Cell Physiology, Faculty of Biology and Biotechnology, Ruhr-University, 44780 Bochum, Germany.
Commun Biol. 2019 Aug 23;2:318. doi: 10.1038/s42003-019-0524-1. eCollection 2019.
Knockout of phosphatase and tensin homolog (PTEN) is neuroprotective and promotes axon regeneration in mature neurons. Elevation of mTOR activity in injured neurons has been proposed as the primary underlying mechanism. Here we demonstrate that PTEN also abrogates the inhibitory activity of GSK3 on collapsin response mediator protein 2 (CRMP2) in retinal ganglion cell (RGC) axons. Moreover, maintenance of GSK3 activity in knockin mice significantly compromised PTEN-mediated optic nerve regeneration as well as the activity of CRMP2, and to a lesser extent, mTOR. These GSK3 mediated negative effects on regeneration were rescued by viral expression of constitutively active CRMP2, despite decreased mTOR activation. knockin or CRMP2 inhibition also decreased PTEN mediated neurite growth of RGCs in culture and disinhibition towards CNS myelin. Thus, the GSK3/CRMP2 pathway is essential for PTEN mediated axon regeneration. These new mechanistic insights may help to find novel strategies to promote axon regeneration.
磷酸酶和张力蛋白同源物（PTEN）的敲除具有神经保护作用，并促进成熟神经元中的轴突再生。有人提出，损伤神经元中 mTOR 活性的升高是主要的潜在机制。在这里，我们证明 PTEN 还可以消除 GSK3 对视网膜神经节细胞（RGC）轴突中 collapsin 反应介质蛋白 2（CRMP2）的抑制活性。此外，在 敲入小鼠中维持 GSK3 的活性会显著损害 PTEN 介导的视神经再生以及 CRMP2 的活性，并且在较小程度上损害 mTOR。尽管 mTOR 激活减少，但病毒表达组成性激活的 CRMP2 可挽救 GSK3 介导的再生的负效应。 敲入或 CRMP2 抑制也会减少 RGC 培养中的 PTEN 介导的神经突生长和对中枢神经系统髓鞘的去抑制作用。因此，GSK3/CRMP2 途径对于 PTEN 介导的轴突再生至关重要。这些新的机制见解可能有助于找到促进轴突再生的新策略。
