Abstract Details

Title Transcriptional control of optic nerve injury associated retinal ganglion cell death

Topic Neuro-ophthalmology/Neuro-otology

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 4-011

Objective To determine the transcriptional network(s) critical for retinal ganglion cell (RGC) death after axonal injury.

Background Optic nerve injury occurs in many neurologic conditions including traumatic, ischemic, inflammatory, and glaucomatous optic neuropathies. Thus, determining the molecular signals that drive degeneration in RGCs after injury could identify promising therapeutic targets for intervention. Two transcription factors, JUN, (a canonical target of the c-Jun N-terminal kinases, JNKs) and DDIT3 (a key mediator of the endoplasmic reticulum stress response) are known to control the majority of pro-apoptotic signaling in RGCs after axonal injury. However, the downstream transcriptional networks controlled by these molecules together are not well defined.

Design/Methods

Three days after optic nerve crush(ONC) injury, RNA was isolated from wild-type mice and mice deficient in Jun, Ddit3, and both Jun and Ddit3. RNA-sequencing was performed using Illumina HiSeq4000 and transcriptional changes in all experimental cohorts were analyzed using a variety of bioinformatic pipelines including RSEM, edgeR and Ingenuity Pathway Analysis. Four eyes were used per genotype per condition.

Results ONC injury led to the differential expression of 1264 genes in wild-type controls animals. Deficiency of Ddit3 or Jun alone prevented approximately 500 and 900 of these changes respectively, while dual deficiency of Jun and Ddit3 prevented changes in all but 286 genes. Axonal injury dependent signaling changes in WT mice, including changes in neuronal and pro-inflammatory signaling such as synaptic long term potentiation (GRIN1, GRIN2A, GRIN3A) and CREB (CAMK2A), acute phase response (TNFRSF1A), and IL-6 signaling (STAT3), were attenuated by Jun deficiency. ATF5 and AVIL were identified as Ddit3 specific downstream changes after ONC.

Conclusions

These results highlight the importance of JUN and DDIT3 in regulating the major transcriptional networks governing apoptotic signaling and subsequent somal degeneration of RGCs after mechanical axonal injury. Furthermore, such study may allow for staging of the pro-degenerative signals following optic nerve injury.

Authors/Disclosures
Stephanie Syc-Mazurek, MD, PhD (Mayo Clinic) PRESENTER	Dr. Syc-Mazurek has a non-compensated relationship as a Editorial Board Resident and Fellows Section with Neurology that is relevant to AAN interests or activities.
	No disclosure on file
	No disclosure on file
	No disclosure on file

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