April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
JNK-dependent JUN Signaling Is Critical To Retinal Ganglion Cell Death After Axonal Injury
Author Affiliations & Notes
  • Jeffrey M. Harder
    Center for Visual Sciences, Flaum Eye Institute,
    Pathology,
    University of Rochester, Rochester, New York
  • Kimberly A. Fernandes
    Center for Visual Sciences, Flaum Eye Institute,
    University of Rochester, Rochester, New York
  • Lin Gan
    Center for Visual Sciences, Flaum Eye Institute,
    University of Rochester, Rochester, New York
  • Richard T. Libby
    Center for Visual Sciences, Flaum Eye Institute,
    Department of Biomedical Genetics,
    University of Rochester, Rochester, New York
  • Footnotes
    Commercial Relationships  Jeffrey M. Harder, None; Kimberly A. Fernandes, None; Lin Gan, None; Richard T. Libby, None
  • Footnotes
    Support  EY018606, Research to Prevent Blindness and Dave Bryant Trust (RTL); EY007125 (JMH)
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 3076. doi:
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    • Get Citation

      Jeffrey M. Harder, Kimberly A. Fernandes, Lin Gan, Richard T. Libby; JNK-dependent JUN Signaling Is Critical To Retinal Ganglion Cell Death After Axonal Injury. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3076.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : The molecular mechanisms that lead to RGC death following a glaucomatous insult are not well defined. JNK pathway activation is one form of stress-induced signaling previously implicated in glaucomatous neurodegeneration. However, the precise components of this multifaceted pathway that cause RGC death are not known. Here, we investigate which JNK isoforms and potential downstream targets are responsible for JNK dependent RGC death after axonal injury.

Methods: : Null alleles of Jnk2, Jnk3, and Jun (floxed allele deleted with Six3-cre) were used to determine if these genes are critical for RGC death after axonal injury. Controlled optic nerve crush (CONC) was performed on wildtype or mutant eyes to injure RGC axons. To assess RGC loss POU4F1+ cells and RGC layer neurons were counted after injury. Immunolabeling of downstream targets, such as pJUN and BIM, was performed to assess JNK pathway activity after injury and in the absence of JNK signaling components.

Results: : We began exploring the importance of JNK signaling in axonally injured RGCs by assessing RGC survival after CONC. Deficiency in either Jnk2 or Jnk3 did not prevent RGC death at 14 days after CONC (P>0.05 for each). However, in Jnk2-/- Jnk3-/- mutant mice RGCs were significantly protected from RGC death 14 days after CONC, when the majority of axonal injury induced RGC death has occurred (given as percent survival of RGC layer neurons compared to unmanipulated eyes of the same genotype, control, 69.1±1.4%, n=5; Jnk2-/- Jnk3-/-, 93.2±2.4%, n=6; P<0.01). This protection was confirmed by counting POU4F1+ cells at 10 days post CONC (P<0.01). Jnk2/3 mutants appeared to have significantly less pJUN than wildtype suggesting the canonical JNK target may be mediating the protection. RGC loss was also significantly delayed in JUN deficient retinas 14 days after CONC (control, 68.4±2.7%, n=5; Jun-/-, 95.4±3.9%, n=5, P<0.01). Interestingly, in both the JNK2/3 and JUN deficient retinas, expression of the proapoptotic Bcl2 family member BIM, a molecule known to be involved in RGC death after axonal injury, was significantly decreased after CONC.

Conclusions: : JNK2 and 3 regulate an important pathway leading from axonal injury to apoptosis in RGCs. This pathway appears to involve the activation of the transcription factor JUN, which in turn regulates the proapoptotic molecule BIM.

Keywords: apoptosis/cell death • ganglion cells • retinal degenerations: cell biology 
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