title: GSK3β regulates AKT-induced central nervous system axon regeneration via an eIF2Bε-dependent, mTORC1-independent pathway.
abstract: Axons fail to regenerate after central nervous system (CNS) injury. Modulation of the PTEN/mTORC1 pathway in retinal ganglion cells (RGCs) promotes axon regeneration after optic nerve injury. Here, we report that AKT activation, downstream of Pten deletion, promotes axon regeneration and RGC survival. We further demonstrate that GSK3β plays an indispensable role in mediating AKT-induced axon regeneration. Deletion or inactivation of GSK3β promotes axon regeneration independently of the mTORC1 pathway, whereas constitutive activation of GSK3β reduces AKT-induced axon regeneration. Importantly, we have identified eIF2Bε as a novel downstream effector of GSK3β in regulating axon regeneration. Inactivation of eIF2Bε reduces both GSK3β and AKT-mediated effects on axon regeneration. Constitutive activation of eIF2Bε is sufficient to promote axon regeneration. Our results reveal a key role of the AKT-GSK3β-eIF2Bε signaling module in regulating axon regeneration in the adult mammalian CNS.
authors.affiliation: Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, United States.
authors.forename: Xinzheng
authors.initials: X
authors.lastname: Guo
authors.affiliation: UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Snider
authors.affiliation: Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, United States.|Department of Neurobiology, Yale University School of Medicine, New Haven, United States.
authors.forename: Bo
authors.identifier: http://orcid.org/0000-0003-2768-9007
authors.initials: B
authors.lastname: Chen
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D020221:Optic Nerve Injuries / Q000473:pathology*; D012038:Regeneration; D012165:Retinal Ganglion Cells / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D046912:Multiprotein Complexes; D000071679:Glycogen Synthase Kinase 3 beta; D000076222:Mechanistic Target of Rapamycin Complex 1; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases
keywords: CNS axon regeneration; axon injury; mouse; neuroscience; signal transduction