AKT-dependent and -independent pathways mediate PTEN deletion-induced CNS axon regeneration
AKT-dependent and -independent pathways mediate PTEN deletion-induced CNS axon regeneration
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AKT依赖和非依赖途径介导PTEN缺失诱导的CNS轴突再生
DOI：
10.1038/s41419-018-1289-z
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发表时间：
2019-02-27
影响因子：
9
通讯作者：
Hu, Yang
中科院分区：
文献类型：
--
作者：
Huang, Haoliang;Miao, Linqing;Hu, Yang
磷酸酶和紧张素同源物（PTEN）可抑制磷脂酰肌醇3-激酶- akt - mtor复合物1 （mTORC1）通路，其缺失可促进中枢神经系统（CNS）轴突再生。先前，我们证明AKT激活足以促进中枢神经系统轴突再生，但其程度低于PTEN缺失。对于PTEN缺失对中枢神经系统轴突的再生作用，AKT是否完全起作用仍存在疑问。本研究表明，阻断AKT或其下游效应物mTORC1和GSK3 β，可显著降低PTEN缺失诱导的小鼠视神经再生，表明AKT依赖性信号通路的必要作用。然而，由于mtorc1介导的反馈抑制，AKT在pten缺失小鼠中仅被轻微激活。PTEN缺失与AKT过表达或GSK3 β缺失相结合可以显著增强轴突再生，这表明轴突再生途径与AKT无关。阐明akt非依赖性通路是制定有效的中枢神经系统轴突再生策略所必需的。
Phosphatase and tensin homolog (PTEN) acts as a brake for the phosphatidylinositol 3-kinase-AKT-mTOR complex 1 (mTORC1) pathway, the deletion of which promotes potent central nervous system (CNS) axon regeneration. Previously, we demonstrated that AKT activation is sufficient to promote CNS axon regeneration to a lesser extent than PTEN deletion. It is still questionable whether AKT is entirely responsible for the regenerative effect of PTEN deletion on CNS axons. Here, we show that blocking AKT or its downstream effectors, mTORC1 and GSK3 beta, significantly reduces PTEN deletion-induced mouse optic nerve regeneration, indicating the necessary role of AKT-dependent signaling. However, AKT is only marginally activated in PTEN-null mice due to mTORC1-mediated feedback inhibition. That combining PTEN deletion with AKT overexpression or GSK3 beta deletion achieves significantly more potent axonal regeneration suggests an AKT-independent pathway for axon regeneration. Elucidating the AKT-independent pathway is required to develop effective strategies for CNS axon regeneration.