July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Downstream transcriptional control of retinal ganglion cell apoptosis after axonal injury
Author Affiliations & Notes
  • Stephanie B. Syc-Mazurek
    Ophthalmology, University of Rochester, Rochester, New York, United States
  • Hongtian Yang
    The Jackson Laboratory, Maine, United States
  • Gareth R Howell
    The Jackson Laboratory, Maine, United States
  • Richard T Libby
    Ophthalmology, University of Rochester, Rochester, New York, United States
  • Footnotes
    Commercial Relationships   Stephanie Syc-Mazurek, None; Hongtian Yang, None; Gareth Howell, None; Richard Libby, None
  • Footnotes
    Support  This work was supported by EY018606 (RTL), Research to Prevent Blindness (an unrestricted grant to the Department of Ophthalmology at the University of Rochester Medical Center), and the Diana Davis Foundation Chair for Glaucoma Research (GRH).
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 656. doi:https://doi.org/
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      Stephanie B. Syc-Mazurek, Hongtian Yang, Gareth R Howell, Richard T Libby; Downstream transcriptional control of retinal ganglion cell apoptosis after axonal injury. Invest. Ophthalmol. Vis. Sci. 2019;60(9):656. doi: https://doi.org/.

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

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Abstract

Purpose : Retinal ganglion cell (RGC) axonal injury is a key pathological event in glaucomatous neurodegeneration. The transcription factors JUN (the target of the c-Jun N-terminal kinases, JNKs) and DDIT/CHOP (a mediator of the endoplasmic reticulum stress response) have been shown to control the majority of pro-apoptotic signaling after mechanical axonal injury in RGCs. The downstream transcriptional networks critical for RGC death controlled by JUN and DDIT, however, are not well defined.

Methods : RNA was isolated from the retinas of wild-type mice and mice deficient in Jun, Ddit3, or both Jun and Ddit3 three days after mechanical optic nerve crush injury (ONC). The contralateral naïve retina from all animals was used as a control. Four eyes per genotype per condition were analyzed. The Illumina HiSeq4000 system was used for RNA-sequencing and bioinformatic pipelines including RSEM, edgeR and Ingenuity Pathway Analysis were used to analyze transcriptional changes in all experimental cohorts. Immunohistochemistry (GFAP, IBA1, CD68) was used to determine potential pro-inflammatory changes after axonal injury.

Results : As compared to wild-type naïve retinas, 1264 genes were differentially expressed in wild-type animals after ONC. Retinas deficient in Ddit3, Jun, or Jun and Ddit3 together differentially expressed 744, 383, and 286 genes respectively after ONC. Jun deficiency attenuated changes in synaptic long-term potentiation (GRIN1, GRIN2A, GRIN3A), CREB signaling (CAMK2A), and HMGB1 signaling (HSPB1, NFKB2). Ddit3 attenuated changes in ATF5 and AVIL. Injury dependent changes in pro-inflammatory signaling (GFAP, CD68, CD44, ITGA5, MMP12, TNFRSF1A, STAT3) were attenuated by Jun and dual Jun and Ddit3 deficiency. Retinas deficient in both Jun and Ddit3 demonstrated diminished inflammatory changes seven days after ONC including decreased GFAP reactivity in Müller glial processes, decreased microglial activation, and decreased CD68 immunostaining.

Conclusions : These results determine the downstream transcriptional networks important for apoptotic signaling and may be important for ordering and staging the pro-degenerative signals after mechanical axonal injury. Furthermore, such study suggests the retinal pro-inflammatory responses after injury may be a secondary response to RGC death.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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