Abstract
In the nearly 10 years since PTEN was identified as a prominent intrinsic inhibitor of CNS axon regeneration, the PTEN negatively regulated PI3K-AKT-mTOR pathway has been intensively explored in diverse models of axon injury and diseases and its mechanism for axon regeneration is becoming clearer. It is therefore timely to summarize current knowledge and discuss future directions of translational regenerative research for neural injury and neurodegenerative diseases. 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 pathway to illuminate the cross-regulating mechanisms in axon regeneration. AKT is the nodal point that coordinates both positive and negative signals to regulate adult CNS axon regeneration through two parallel pathways, activating mTORC1 and inhibiting GSK3ββ. Activation of mTORC1 or its effector S6K1 alone can only slightly promote axon regeneration, whereas blocking mTORC1 significantly prevent axon regeneration, suggesting the necessary role of mTORC1 in axon regeneration. However, mTORC1/S6K1-mediated feedback inhibition prevents potent AKT activation, which suggests 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 eventually to safe and effective regenerative strategies for CNS repair.
Highlights
Axon injury is a frequent consequence of trauma and a common early feature of CNS degenerative diseases causing life-long neurological deficits
Genetic manipulations in retinal ganglion cell (RGC) provide a molecular dissection of the phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K)-AKTmTORC1/GSK3β, and PI3K-mTORC2-AKT-mammalian target of rapamycin complex 1 (mTORC1)/GSK3β pathways and definitively determine the linear and parallel signals that contribute to CNS axon regeneration (Figure 2)
The balance between mTORC1 and mTORC2’s activities after PT3K activation converges on AKT phosphorylation of T308 and S473, which in turn control the activation of mTORC1 and inhibition of GSK3β that act in parallel and synergistically downstream of AKT to promote potent CNS axon regeneration. mTORC1/S6 kinase (S6K) functions as feedback inhibition of PI3K signaling (Laplante and Sabatini, 2012) to keep AKT and mTORC1 on check (Yang et al, 2014), which suggests that another proactive signal originating from PTEN deletion may trigger the neuron-intrinsic growth capability (Hu, 2015)
Summary
Axon injury is a frequent consequence of trauma and a common early feature of CNS degenerative diseases causing life-long neurological deficits. Injuries of CNS axons often result in loss of vital functions because CNS axons fail to regenerate in adult mammals (Schwab and Bartholdi, 1996; Goldberg et al, 2002b; Fitch and Silver, 2008). Both the diminished intrinsic regenerative capacity of mature neurons (Park et al, 2010) and the inhibitory environment of the adult CNS (Yiu and He, 2006) contribute to the growth failure. Neutralizing extracellular inhibitory molecules genetically or pharmacologically yields only limited regeneration and functional recovery (Lee et al, 2010), highlighting the critical importance of neuron-intrinsic factors (Benowitz et al, 2017). To explore the intrinsic regenerative signaling molecules, mouse retinal ganglion cell (RGC) and optic nerve (ON) provide a valuable in vivo neural injury system that is relatively simple but robustly replicates CNS traumatic injury and permits straightforward interpretation (Figure 1)
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