Haoliang Huang1, Simran Kaur1, Yang Hu1. 1. Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, USA.
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.
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.
Authors: Kimberly J Christie; Christine A Webber; Jose A Martinez; Bhagat Singh; Douglas W Zochodne Journal: J Neurosci Date: 2010-07-07 Impact factor: 6.167
Authors: Yuanquan Song; Kassandra M Ori-McKenney; Yi Zheng; Chun Han; Lily Yeh Jan; Yuh Nung Jan Journal: Genes Dev Date: 2012-07-03 Impact factor: 11.361