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  • Title: Lab review: Molecular dissection of the signal transduction pathways associated with PTEN deletion-induced optic nerve regeneration.
    Author: Huang H, Kaur S, Hu Y.
    Journal: Restor Neurol Neurosci; 2019; 37(6):545-552. PubMed ID: 31839616.
    Abstract:
    BACKGROUND: Permanent loss of vital functions after central nervous system (CNS) injury occurs in part because axons in the adult mammalian CNS do not regenerate after injury. PTEN was identified as a prominent intrinsic inhibitor of CNS axon regeneration about 10 years ago. The PTEN negatively regulated PI3K-AKT-mTOR pathway, which has been intensively explored in diverse models of axon injury and diseases and its mechanism for axon regeneration is becoming clearer. OBJECTIVE: It is timely to summarize current knowledge about the PTEN/AKT/mTOR pathway and discuss future directions of translational regenerative research for neural injury and neurodegenerative diseases. METHODS: Using mouse optic nerve crush as an in vivo retinal ganglion cell axon injury model, we have conducted an extensive molecular dissection of the PI3K-AKT-mTORC1/mTORC2 pathway to illuminate the cross-regulating mechanisms in axon regeneration. RESULTS: AKT is the nodal point that coordinates both positive (PI3K-PDK1-pAKT-T308) and negative (PI3K-mTORC2-pAKT-S473) signals to regulate adult CNS axon regeneration through two parallel pathways, activating mTORC1 and inhibiting GSK3β. However, mTORC1/S6K1-mediated feedback inhibition after PTEN deletion prevents potent AKT activation. CONCLUSIONS: A key permissive signal from an unidentified AKT-independent pathway is required for stimulating the neuron-intrinsic growth machinery. Future studies into this complex neuron-intrinsic balancing mechanism involving necessary and permissive signals for axon regeneration is likely to lead to safe and effective regenerative strategies for CNS repair.
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