title: mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system.
abstract: Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that involve the downstream effectors of PI3K, AKT and the two mTOR complexes (mTORC1 and mTORC2). We found that the predominant AKT isoform in CNS, AKT3, induces much more robust axon regeneration than AKT1 and that activation of mTORC1 and inhibition of GSK3β are two critical parallel pathways for AKT-induced axon regeneration. Surprisingly, phosphorylation of T308 and S473 of AKT play opposite roles in GSK3β phosphorylation and inhibition, by which mTORC2 and pAKT-S473 negatively regulate axon regeneration. Thus, our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration.
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, United States.
authors.forename: Linqing
authors.initials: L
authors.lastname: Miao
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, United States.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, United States.
authors.forename: Haoliang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, United States.
authors.forename: Feisi
authors.initials: F
authors.lastname: Liang
authors.affiliation: Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, United States.
authors.forename: Chen
authors.initials: C
authors.lastname: Ling
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, United States.|Department of Anatomy and Cell Biology, Temple University Lewis Katz School of Medicine, Philadelphia, United States.
authors.forename: Yang
authors.identifier: http://orcid.org/0000-0002-7980-1649
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002490:Central Nervous System / Q000502:physiology*; D005786:Gene Expression Regulation; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012038:Regeneration; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; C491753:Akt3 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: AKT; GSK3; axon regeneration; mTORC1; mTORC2; mouse; neuroscience; optic nerve