GSK3-CRMP2 signaling mediates axonal regeneration induced by Pten knockout
GSK3-CRMP2 signaling mediates axonal regeneration induced by Pten knockout
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DOI：
10.1038/s42003-019-0524-1
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发表时间：
2019-08-23
影响因子：
5.9
通讯作者：
Fischer, Dietmar
中科院分区：
文献类型：
--
作者：
Leibinger, Marco;Hilla, Alexander M.;Fischer, Dietmar
磷酸酶和张力蛋白同源物 (PTEN-/-) 的敲除具有神经保护作用，并促进成熟神经元的轴突再生。受损神经元中 mTOR 活性的升高被认为是主要的潜在机制。在这里，我们证明 PTEN-/- 还消除了 GSK3 对视网膜神经节细胞 (RGC) 轴突中塌陷素反应介导蛋白 2 (CRMP2) 的抑制活性。此外，Gsk3(S/A)敲入小鼠中GSK3活性的维持显着损害PTEN-/-介导的视神经再生以及CRMP2的活性，并在较小程度上损害mTOR。尽管 mTOR 激活减少，但这些 GSK3(S/A) 介导的对再生的负面影响可以通过组成型活性 CRMP2(T/A) 的病毒表达来挽救。 Gsk3(S/A) 敲入或 CRMP2 抑制也降低了培养物中 PTEN-/- 介导的 RGC 神经突生长以及对 CNS 髓磷脂的去抑制。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。
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 Gsk3(S/A) knockin mice significantly compromised PTEN-/--mediated optic nerve regeneration as well as the activity of CRMP2, and to a lesser extent, mTOR. These GSK3(S/A) mediated negative effects on regeneration were rescued by viral expression of constitutively active CRMP2(T/A), despite decreased mTOR activation. Gsk3(S/A) 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.