title: DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury.
abstract: Injury to retinal ganglion cell (RGC) axons triggers rapid activation of Jun N-terminal kinase (JNK) signaling, a major prodeath pathway in injured RGCs. Of the multiple kinases that can activate JNK, dual leucine kinase (Dlk) is known to regulate both apoptosis and Wallerian degeneration triggered by axonal insult. Here we tested the importance of Dlk in regulating somal and axonal degeneration of RGCs following axonal injury. Removal of DLK from the developing optic cup did not grossly affect developmental RGC death or inner plexiform layer organization. In the adult, Dlk deficiency significantly delayed axonal-injury induced RGC death. The activation of JUN was also attenuated in Dlk deficient retinas. Dlk deficiency attenuated the activation of the somal pool of JNK but did not prevent activation of the axonal pool of JNK after axonal injury, indicating that JNK activation in different cellular compartments of an RGC following axonal injury is regulated by distinct upstream kinases. In contrast to its robust influence on somal degeneration, Dlk deficiency did not alter RGC axonal degeneration after axonal injury as assessed using physiological readouts of optic nerve function.
authors.affiliation: Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Fernandes
authors.affiliation: Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Harder
authors.affiliation: The Jackson Laboratory and Howard Hughes Medical Institute, Bar Harbor, ME 04609, USA.
authors.forename: Simon W
authors.initials: SW
authors.lastname: John
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Shrager
authors.affiliation: Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA; The Center for Visual Sciences, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: richard_libby@urmc.rochester.edu.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency* / Q000235:genetics; D008822:Mice, Transgenic; D020221:Optic Nerve Injuries / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D012160:Retina / Q000201:enzymology / Q000254:growth & development / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D014855:Wallerian Degeneration / Q000201:enzymology* / Q000473:pathology
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12
keywords: Axonopathy; Cell death; DLK; Glaucoma; MAPK; Wlds; cJUN