GSK3β regulates AKT-induced central nervous system axon regeneration via an eIF2Bε-dependent, mTORC1-independent pathway.
GSK3β regulates AKT-induced central nervous system axon regeneration via an eIF2Bε-dependent, mTORC1-independent pathway.
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作者：
Guo X;Snider WD;Chen B
中枢神经系统（CNS）损伤后轴突不能再生。视网膜神经节细胞（RGCs）中PTEN/mTORC1通路的调节促进视神经损伤后轴突再生。在这里，我们报道了Pten缺失下游的AKT激活促进轴突再生和RGC存活。我们进一步证明GSK3β在介导akt诱导的轴突再生中起着不可或缺的作用。GSK3β的缺失或失活可独立于mTORC1途径促进轴突再生，而GSK3β的组成性激活可减少akt诱导的轴突再生。重要的是，我们已经确定eif2bb是GSK3β调节轴突再生的一种新的下游效应物。eif2bb的失活降低了GSK3β和akt介导的轴突再生作用。eif2bb的组成激活足以促进轴突再生。我们的研究结果揭示了akt - gsk3 β- eif2bb信号模块在调节成年哺乳动物中枢神经系统轴突再生中的关键作用。DOI: http://dx.doi.org/10.7554/eLife.11903.001中枢神经系统由构成大脑、视网膜和脊髓的神经元组成。神经元沿着一种叫做轴突的电缆状结构传递电信号。然而，轴突不能自我再生，因此挤压或切断轴突的损伤可能导致永久性损伤。发生这种情况有两个原因：神经元不像其他细胞一样具有再生能力，中枢神经系统的环境限制了细胞的生长。视神经把眼睛的视觉信息传递给大脑。对视神经受损小鼠的研究表明，缺乏PTEN蛋白的神经元轴突有可能再生。这些研究揭示了消除PTEN有助于促进轴突再生的一种分子途径。现在，Guo等人发现了另一种独立的途径，通过消除PTEN有助于促进受损小鼠视神经轴突再生。这条通路始于一种叫做AKT的促生长酶，这种酶在缺乏PTEN的神经元中被激活。事实上，给老鼠注射一种活性的这种酶能使视神经受损的老鼠的视神经纤维再生。进一步的实验表明，AKT激活了另一种名为GSK3β的酶作用于名为eif2bb的蛋白质的途径。未来的挑战是同时操纵与轴突再生相关的不同信号通路，以研究这种联合方法是否有助于修复中枢神经系统的损伤。DOI: http://dx.doi.org/10.7554/eLife.11903.002
Axons fail to regenerate after central nervous system (CNS) injury. Modulation of the PTEN/mTORC1 pathway in retinal ganglion cells (RGCs) promotes axon regeneration after optic nerve injury. Here, we report that AKT activation, downstream of Pten deletion, promotes axon regeneration and RGC survival. We further demonstrate that GSK3β plays an indispensable role in mediating AKT-induced axon regeneration. Deletion or inactivation of GSK3β promotes axon regeneration independently of the mTORC1 pathway, whereas constitutive activation of GSK3β reduces AKT-induced axon regeneration. Importantly, we have identified eIF2Bε as a novel downstream effector of GSK3β in regulating axon regeneration. Inactivation of eIF2Bε reduces both GSK3β and AKT-mediated effects on axon regeneration. Constitutive activation of eIF2Bε is sufficient to promote axon regeneration. Our results reveal a key role of the AKT-GSK3β-eIF2Bε signaling module in regulating axon regeneration in the adult mammalian CNS. DOI: http://dx.doi.org/10.7554/eLife.11903.001 The central nervous system consists of the neurons that make up the brain, retina, and spinal cord. Neurons transmit electrical signals along a cable-like structure called an axon. However, an axon cannot regenerate itself, and so injuries that crush or sever the axons can lead to permanent damage. This happens for two reasons: neurons don’t have the same regenerative ability as other cells, and the environment in the central nervous system restricts cell growth. The optic nerve transmits visual information from the eye to the brain. Studies in mice with a damaged optic nerve show that it is possible to regenerate the axons of neurons that lack a protein known as PTEN. These studies revealed one molecular pathway by which eliminating PTEN helps to boost the regrowth of axons. Now, Guo et al. identify another independent pathway by which eliminating PTEN helps promote axon regeneration in damaged mouse optic nerves. This pathway starts with a growth-promoting enzyme called AKT, which is turned on in neurons that lack PTEN. Indeed, injecting mice with an active form of this enzyme caused the optic nerve fiber to regrow in mice whose optic nerve had been crushed. Further experiments revealed that AKT activates a pathway in which another enzyme called GSK3β acts on a protein called eIF2Bε. A future challenge is to simultaneously manipulate the different signaling pathways that have been linked to axon regrowth to investigate whether this combined approach could help repair damage to the central nervous system. DOI: http://dx.doi.org/10.7554/eLife.11903.002