Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA.
Shriners Center for Neural Repair and Rehabilitation, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
Cell Death Dis. 2019 Feb 27;10(3):203. doi: 10.1038/s41419-018-1289-z.
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 GSK3β, 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 GSK3β 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.
磷酸酶和张力蛋白同源物 (PTEN) 作为磷脂酰肌醇 3-激酶-AKT-mTOR 复合物 1 (mTORC1) 通路的制动器，其缺失可促进强大的中枢神经系统 (CNS) 轴突再生。此前，我们证明 AKT 激活足以在较小程度上促进 CNS 轴突再生，而不是 PTEN 缺失。AKT 是否完全负责 PTEN 缺失对 CNS 轴突的再生作用仍存在疑问。在这里，我们表明阻断 AKT 或其下游效应物 mTORC1 和 GSK3β 可显著减少 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性。然而，由于 mTORC1 介导的反馈抑制，PTEN 缺失小鼠中的 AKT 仅被轻度激活。联合使用 PTEN 缺失与 AKT 过表达或 GSK3β 缺失可实现更有效的轴突再生，这表明存在 AKT 非依赖性的轴突再生途径。阐明 AKT 非依赖性途径对于开发中枢神经系统轴突再生的有效策略是必要的。
