title: Hyperactivated Stat3 boosts axon regeneration in the CNS.
abstract: Axonal regeneration after spinal cord injury (SCI) is intrinsically and extrinsically inhibited by multiple factors. One major factor contributing to intrinsic regeneration failure is the inability of mature neurons in the central nervous system (CNS) to activate regeneration-associated transcription factors (TFs) post-injury. A prior study identified TFs overexpressed in neurons of the peripheral nervous system (PNS) compared to the CNS; some of these could be involved in the ability of PNS neurons to regenerate. Of these, signal transducer and activator of transcription 3 (STAT3), as well its downstream regeneration-associated targets, showed a significant upregulation in PNS neurons relative to CNS neurons, and a constitutively active variant of Stat3 (Stat3CA) promoted neurite growth when expressed in cerebellar neurons (Lerch et al., 2012; Smith et al., 2011). To further enhance STAT3's neurite outgrowth enhancing activity, Stat3CA was fused with a viral activation domain (VP16). VP16 hyperactivates TFs by recruiting transcriptional co-factors to the DNA binding domain (Hirai et al., 2010). Overexpression of this VP16-Stat3CA chimera in primary cortical neurons led to a significant increase of neurite outgrowth as well as Stat3 transcriptional activity in vitro. Furthermore, in vivo transduction of retinal ganglion cells (RGCs) with AAV constructs expressing VP16-Stat3CA resulted in regeneration of optic nerve axons after injury, to a greater degree than for those expressing Stat3CA alone. These findings confirm and extend the concept that overexpression of hyperactivated transcription factors identified as functioning in PNS regeneration can promote axon regeneration in the CNS.
authors.affiliation: Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: s.mehta8@med.miami.edu.
authors.forename: Saloni T
authors.initials: ST
authors.lastname: Mehta
authors.affiliation: Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai, 200080, China. Electronic address: xluo@med.miami.edu.
authors.forename: Xueting
authors.initials: X
authors.lastname: Luo
authors.affiliation: Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: kpark@med.miami.edu.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Park
authors.affiliation: Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Center for Computational Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: jbixby@med.miami.edu.
authors.forename: John L
authors.initials: JL
authors.lastname: Bixby
authors.affiliation: Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Center for Computational Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: vlemmon@med.miami.edu.
authors.forename: Vance P
authors.initials: VP
authors.lastname: Lemmon
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology*; D002540:Cerebral Cortex / Q000166:cytology; D002772:Cholera Toxin / Q000633:toxicity; D005260:Female; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009416:Nerve Regeneration / Q000502:physiology*; D016501:Neurites; D020221:Optic Nerve Injuries / Q000473:pathology*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: D017405:Herpes Simplex Virus Protein Vmw65; D050796:STAT3 Transcription Factor; D002772:Cholera Toxin
keywords: Activation domain; Axon regeneration; Neurite outgrowth; Optic nerve; Transcription factor; VP16