title: Misguidance and modulation of axonal regeneration by Stat3 and Rho/ROCK signaling in the transparent optic nerve.
abstract: The use of the visual system played a major role in the elucidation of molecular mechanisms controlling axonal regeneration in the injured CNS after trauma. In this model, CNTF was shown to be the most potent known neurotrophic factor for axonal regeneration in the injured optic nerve. To clarify the role of the downstream growth regulator Stat3, we analyzed axonal regeneration and neuronal survival after an optic nerve crush in adult mice. The infection of retinal ganglion cells with adeno-associated virus serotype 2 (AAV2) containing wild-type (Stat3-wt) or constitutively active (Stat3-ca) Stat3 cDNA promoted axonal regeneration in the injured optic nerve. Axonal growth was analyzed in whole-mounted optic nerves in three dimensions (3D) after tissue clearing. Surprisingly, with AAV2.Stat3-ca stimulation, axons elongating beyond the lesion site displayed very irregular courses, including frequent U-turns, suggesting massive directionality and guidance problems. The pharmacological blockade of ROCK, a key signaling component for myelin-associated growth inhibitors, reduced axonal U-turns and potentiated AAV2.Stat3-ca-induced regeneration. Similar results were obtained after the sustained delivery of CNTF in the axotomized retina. These results show the important role of Stat3 in the activation of the neuronal growth program for regeneration, and they reveal that axonal misguidance is a key limiting factor that can affect long-distance regeneration and target interaction after trauma in the CNS. The correction of axonal misguidance was associated with improved long-distance axon regeneration in the injured adult CNS.
authors.affiliation: Brain Research Institute, University of Zürich and Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland. pernet@hifo.uzh.ch
authors.forename: V
authors.initials: V
authors.lastname: Pernet
authors.forename: S
authors.initials: S
authors.lastname: Joly
authors.forename: N
authors.initials: N
authors.lastname: Jordi
authors.forename: D
authors.initials: D
authors.lastname: Dalkara
authors.forename: A
authors.initials: A
authors.lastname: Guzik-Kornacka
authors.forename: J G
authors.initials: JG
authors.lastname: Flannery
authors.forename: M E
authors.initials: ME
authors.lastname: Schwab
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D001060:Aporphines; D001369:Axons / Q000502:physiology*; D002470:Cell Survival; D020934:Ciliary Neurotrophic Factor / Q000502:physiology; D000229:Dependovirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration; D009900:Optic Nerve / Q000166:cytology / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D012165:Retinal Ganglion Cells / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000577:Amides; D001060:Aporphines; D020934:Ciliary Neurotrophic Factor; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C108830:Y 27632; C069090:lysicamine; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins