{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T15:34:21Z","timestamp":1792683261669,"version":"4.5.0"},"reference-count":50,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2016,3,14]],"date-time":"2016-03-14T00:00:00Z","timestamp":1457913600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,3,14]],"date-time":"2016-03-14T00:00:00Z","timestamp":1457913600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,3,14]],"date-time":"2016-03-14T00:00:00Z","timestamp":1457913600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005326","name":"Yale University","doi-asserted-by":"publisher","award":["New Faculty Award"],"award-info":[{"award-number":["New Faculty Award"]}],"id":[{"id":"10.13039\/100005326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","award":["Unrestricted fund to the Yale Eye Center"],"award-info":[{"award-number":["Unrestricted fund to the Yale Eye Center"]}],"id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>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 GSK3\u03b2 plays an indispensable role in mediating AKT-induced axon regeneration. Deletion or inactivation of GSK3\u03b2 promotes axon regeneration independently of the mTORC1 pathway, whereas constitutive activation of GSK3\u03b2 reduces AKT-induced axon regeneration. Importantly, we have identified eIF2B\u03b5 as a novel downstream effector of GSK3\u03b2 in regulating axon regeneration. Inactivation of eIF2B\u03b5 reduces both GSK3\u03b2 and AKT-mediated effects on axon regeneration. Constitutive activation of eIF2B\u03b5 is sufficient to promote axon regeneration. Our results reveal a key role of the AKT-GSK3\u03b2-eIF2B\u03b5 signaling module in regulating axon regeneration in the adult mammalian CNS.<\/jats:p>","DOI":"10.7554\/elife.11903","type":"journal-article","created":{"date-parts":[[2016,3,14]],"date-time":"2016-03-14T08:59:56Z","timestamp":1457945996000},"source":"Crossref","is-referenced-by-count":91,"title":["GSK3\u03b2 regulates AKT-induced central nervous system axon regeneration via an eIF2B\u03b5-dependent, mTORC1-independent pathway"],"prefix":"10.7554","volume":"5","author":[{"given":"Xinzheng","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William D","family":"Snider","sequence":"additional","affiliation":[{"name":"UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2768-9007","authenticated-orcid":true,"given":"Bo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, United States"},{"name":"Department of Neurobiology, Yale University School of Medicine, New Haven, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2016,3,14]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"10584","DOI":"10.1074\/jbc.M311055200","article-title":"Structure of the Catalytic Fragment of Translation Initiation Factor 2B and Identification of a Critically Important Catalytic Residue","volume":"279","author":"Boesen","year":"2004","journal-title":"Journal of Biological Chemistry"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.ceb.2009.02.002","article-title":"PIKKing on PKB: regulation of PKB activity by phosphorylation","volume":"21","author":"Bozulic","year":"2009","journal-title":"Current Opinion in Cell Biology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1083\/jcb.200503162","article-title":"Dynamic cycling of eIF2 through a large eIF2B-containing cytoplasmic body","volume":"170","author":"Campbell","year":"2005","journal-title":"The Journal of Cell Biology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"187","DOI":"10.2174\/156800908784293659","article-title":"The PTEN\/PI3K\/AKT Signalling Pathway in Cancer, Therapeutic Implications","volume":"8","author":"Carnero","year":"2008","journal-title":"Current Cancer Drug Targets"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"13439","DOI":"10.1523\/JNEUROSCI.2039-12.2012","article-title":"Spatially Coordinated Kinase Signaling Regulates Local Axon Degeneration","volume":"32","author":"Chen","year":"2012","journal-title":"Journal of Neuroscience"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1038\/378785a0","article-title":"Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B","volume":"378","author":"Cross","year":"1995","journal-title":"Nature"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"9149","DOI":"10.1073\/pnas.1119449109","article-title":"Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors","volume":"109","author":"de Lima","year":"2012","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"8914","DOI":"10.1523\/JNEUROSCI.1178-08.2008","article-title":"Inactivation of Glycogen Synthase Kinase 3 Promotes Axonal Growth and Recovery in the CNS","volume":"28","author":"Dill","year":"2008","journal-title":"Journal of Neuroscience"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"8498","DOI":"10.1073\/pnas.92.18.8498","article-title":"Role of glycogen synthase kinase 3 beta as a negative regulator of dorsoventral axis formation in Xenopus embryos","volume":"92","author":"Dominguez","year":"1995","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"10228","DOI":"10.1073\/pnas.93.19.10228","article-title":"Expression and characterization of glycogen synthase kinase-3 mutants and their effect on glycogen synthase activity in intact cells","volume":"93","author":"Eldar-Finkelman","year":"1996","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"8726","DOI":"10.1523\/JNEUROSCI.2774-04.2004","article-title":"Switching Mature Retinal Ganglion Cells to a Robust Growth State in Vivo: Gene Expression and Synergy with RhoA Inactivation","volume":"24","author":"Fischer","year":"2004","journal-title":"Journal of Neuroscience"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1042\/BST0340022","article-title":"The large spectrum of eIF2B-related diseases","volume":"34","author":"Fogli","year":"2006","journal-title":"Biochemical Society Transactions"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"2134","DOI":"10.1093\/brain\/awr142","article-title":"The histone acetyltransferase p300 promotes intrinsic axonal regeneration","volume":"134","author":"Gaub","year":"2011","journal-title":"Brain"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"2448","DOI":"10.1093\/brain\/awq180","article-title":"A mouse model for eukaryotic translation initiation factor 2B-leucodystrophy reveals abnormal development of brain white matter","volume":"133","author":"Geva","year":"2010","journal-title":"Brain"},{"key":"bib15","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5561","article-title":"Sustained GSK3 activity markedly facilitates nerve regeneration","volume":"5","author":"Gobrecht","year":"2014","journal-title":"Nature Communications"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1101\/gad.1212704","article-title":"Upstream and downstream of mTOR","volume":"18","author":"Hay","year":"2004","journal-title":"Genes & Development"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1038\/35039559","article-title":"Regenerating the damaged central nervous system","volume":"407","author":"Horner","year":"2000","journal-title":"Nature"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1038\/nrn2870","article-title":"GSK3 signalling in neural development","volume":"11","author":"Hur","year":"2010","journal-title":"Nature Reviews Neuroscience"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"1968","DOI":"10.1101\/gad.17015911","article-title":"GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules","volume":"25","author":"Hur","year":"2011","journal-title":"Genes & Development"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1016\/j.neuron.2006.10.031","article-title":"Essential Roles for GSK-3s and GSK-3-Primed Substrates in Neurotrophin-Induced and Hippocampal Axon Growth","volume":"52","author":"Kim","year":"2006","journal-title":"Neuron"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1038\/nrn1557","article-title":"Biochemical mechanisms for translational regulation in synaptic plasticity","volume":"5","author":"Klann","year":"2004","journal-title":"Nature Reviews Neuroscience"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"31372","DOI":"10.1074\/jbc.271.49.31372","article-title":"Expression of a Constitutively Active Akt Ser\/Thr Kinase in 3T3-L1 Adipocytes Stimulates Glucose Uptake and Glucose Transporter 4 Translocation","volume":"271","author":"Kohn","year":"1996","journal-title":"Journal of Biological Chemistry"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1126\/science.1115462","article-title":"EGFR Activation Mediates Inhibition of Axon Regeneration by Myelin and Chondroitin Sulfate Proteoglycans","volume":"310","author":"Koprivica","year":"2005","journal-title":"Science"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"15654","DOI":"10.1523\/JNEUROSCI.4340-10.2010","article-title":"Long-Distance Axon Regeneration in the Mature Optic Nerve: Contributions of Oncomodulin, cAMP, and pten Gene Deletion","volume":"30","author":"Kurimoto","year":"2010","journal-title":"Journal of Neuroscience"},{"key":"bib25","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1523\/JNEUROSCI.20-12-04615.2000","article-title":"Lens injury stimulates axon regeneration in the mature rat optic nerve","volume":"20","author":"Leon","year":"2000","journal-title":"Journal of Neuroscience"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1038\/nn.2603","article-title":"PTEN deletion enhances the regenerative ability of adult corticospinal neurons","volume":"13","author":"Liu","year":"2010","journal-title":"Nature Neuroscience"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1146\/annurev-neuro-061010-113723","article-title":"Neuronal Intrinsic Mechanisms of Axon Regeneration","volume":"34","author":"Liu","year":"2011","journal-title":"Annual Review of Neuroscience"},{"key":"bib28","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2012.00003","article-title":"Coordinating Gene Expression and Axon Assembly to Control Axon Growth: Potential Role of GSK3 Signaling","volume":"5","author":"Liu","year":"2012","journal-title":"Frontiers in Molecular Neuroscience"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/1741-7007-12-47","article-title":"Neuronal deletion of GSK3\u03b2 increases microtubule speed in the growth cone and enhances axon regeneration via CRMP-2 and independently of MAP1B and CLASP2","volume":"12","author":"Liz","year":"2014","journal-title":"BMC Biology"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/S1535-6108(03)00248-4","article-title":"Targeting the PI3K-Akt pathway in human cancer","volume":"4","author":"Luo","year":"2003","journal-title":"Cancer Cell"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","article-title":"AKT\/PKB Signaling: Navigating Downstream","volume":"129","author":"Manning","year":"2007","journal-title":"Cell"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1126\/science.1175737","article-title":"KLF Family Members Regulate Intrinsic Axon Regeneration Ability","volume":"326","author":"Moore","year":"2009","journal-title":"Science"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1084\/jem.20131780","article-title":"B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS","volume":"211","author":"O\u2019Donovan","year":"2014","journal-title":"The Journal of Experimental Medicine"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1128\/MCB.22.2.578-586.2002","article-title":"Role of Translation Initiation Factor 2B in Control of Cell Survival by the Phosphatidylinositol 3-Kinase\/Akt\/Glycogen Synthase Kinase 3 Signaling Pathway","volume":"22","author":"Pap","year":"2002","journal-title":"Molecular and Cellular Biology"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1126\/science.1161566","article-title":"Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN\/mTOR Pathway","volume":"322","author":"Park","year":"2008","journal-title":"Science"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"6314","DOI":"10.1128\/MCB.00763-08","article-title":"Tissue-Specific Role of Glycogen Synthase Kinase 3 in Glucose Homeostasis and Insulin Action","volume":"28","author":"Patel","year":"2008","journal-title":"Molecular and Cellular Biology"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1042\/BST0331487","article-title":"eIF2B, a mediator of general and gene-specific translational control","volume":"33","author":"Pavitt","year":"2005","journal-title":"Biochemical Society Transactions"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1146\/annurev.pharmtox.41.1.789","article-title":"Molecular targets of lithium action","volume":"41","author":"Phiel","year":"2001","journal-title":"Annual Review of Pharmacology and Toxicology"},{"key":"bib39","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3690","article-title":"PI3K\u2013GSK3 signalling regulates mammalian axon regeneration by inducing the expression of Smad1","volume":"4","author":"Saijilafu","year":"2013","journal-title":"Nature Communications"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1016\/j.neuron.2009.11.021","article-title":"SOCS3 Deletion Promotes Optic Nerve Regeneration in Vivo","volume":"64","author":"Smith","year":"2009","journal-title":"Neuron"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1111\/j.1471-4159.2010.06988.x","article-title":"Evidence that glycogen synthase kinase-3 isoforms have distinct substrate preference in the brain","volume":"115","author":"Soutar","year":"2010","journal-title":"Journal of Neurochemistry"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/nature10594","article-title":"Sustained axon regeneration induced by co-deletion of PTEN and SOCS3","volume":"480","author":"Sun","year":"2011","journal-title":"Nature"},{"key":"bib43","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/505607","article-title":"What Are the bona fide GSK3 Substrates?","volume":"2011","author":"Sutherland","year":"2011","journal-title":"International Journal of Alzheimer's Disease"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"4349","DOI":"10.1093\/emboj\/20.16.4349","article-title":"Eukaryotic initiation factor 2B: identification of multiple phosphorylation sites in the epsilon-subunit and their functions in vivo","volume":"20","author":"Wang","year":"2001","journal-title":"The EMBO Journal"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1128\/MCB.01512-07","article-title":"A Novel Mechanism for the Control of Translation Initiation by Amino Acids, Mediated by Phosphorylation of Eukaryotic Initiation Factor 2B","volume":"28","author":"Wang","year":"2008","journal-title":"Molecular and Cellular Biology"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"4039","DOI":"10.1073\/pnas.1211074110","article-title":"DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury","volume":"110","author":"Watkins","year":"2013","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"5416","DOI":"10.1038\/ncomms6416","article-title":"The mTORC1 effectors S6K1 and 4E-BP play different roles in CNS axon regeneration","volume":"5","author":"Yang","year":"2014","journal-title":"Nature Communications"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1038\/nrn1956","article-title":"Glial inhibition of CNS axon regeneration","volume":"7","author":"Yiu","year":"2006","journal-title":"Nature Reviews Neuroscience"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/j.bbrc.2013.12.037","article-title":"Akt-independent GSK3 inactivation downstream of PI3K signaling regulates mammalian axon regeneration","volume":"443","author":"Zhang","year":"2014","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1016\/j.neuron.2004.05.011","article-title":"NGF-Induced Axon Growth Is Mediated by Localized Inactivation of GSK-3\u03b2 and Functions of the Microtubule Plus End Binding Protein APC","volume":"42","author":"Zhou","year":"2004","journal-title":"Neuron"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/11903\/elife-11903-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/11903\/elife-11903-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/11903","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:47:22Z","timestamp":1697057242000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/11903"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,14]]},"references-count":50,"alternative-id":["10.7554\/eLife.11903"],"URL":"https:\/\/doi.org\/10.7554\/elife.11903","archive":["CLOCKSS"],"relation":{"has-review":[{"id-type":"doi","id":"10.7554\/eLife.11903.022","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.11903.023","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,14]]},"article-number":"e11903"}}