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Examination of Anatomical Features of Retinal Ganglion Cells Under N-methyl-D-aspartic Acid (NMDA)-induced Excitotoxicity
Published on: September 19, 2025
JUN regulates early transcriptional responses to axonal injury in retinal ganglion cells
Kimberly A Fernandes1, Jeffrey M Harder, Jessica Kim
1Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY, USA.
Abstract:
The AP1 family transcription factor JUN is an important molecule in the neuronal response to injury. In retinal ganglion cells (RGCs), JUN is upregulated soon after axonal injury and disrupting JUN activity delays RGC death. JUN is known to participate in the control of many different injury response pathways in neurons, including pathways controlling cell death and axonal regeneration. The role of JUN in regulating genes involved in cell death, ER stress, and regeneration was tested to determine the overall importance of JUN in regulating RGC response to axonal injury. Genes from each of these pathways were transcriptionally controlled following axonal injury and Jun deficiency altered the expression of many of these genes. The differentially expressed genes included, Atf3, Ddit3, Ecel1, Gadd45α, Gal, Hrk, Pten, Socs3, and Sprr1a. Two of these genes, Hrk and Atf3, were tested for importance in RGC death using null alleles of each gene. Disruption of the prodeath Bcl2 family member Hrk did not affect the rate or amount of RGC death after axonal trauma. Deficiency in the ATF/CREB family transcription factor Atf3 did lessen the amount of RGC death after injury, though it did not provide long term protection to RGCs. Since JUN's dimerization partner determines its transcriptional targets, the expression of several candidate AP1 family members were examined. Multiple AP1 family members were induced by axonal injury and had a different expression profile in Jun deficient retinas compared to wildtype retinas (Fosl1, Fosl2 and Jund). Overall, JUN appears to play a multifaceted role in regulating RGC response to axonal injury.
Insights
The transcription factor JUN is crucial for retinal ganglion cell (RGC) injury response. JUN influences cell death and regeneration pathways, with its absence altering gene expression and RGC survival after axonal injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- The AP1 family transcription factor JUN plays a key role in neuronal injury responses.
- JUN is upregulated in retinal ganglion cells (RGCs) post-axonal injury, and its inhibition delays RGC death.
Purpose of the Study:
- To investigate JUN's role in regulating genes involved in RGC cell death, ER stress, and axonal regeneration.
- To determine the overall importance of JUN in the RGC response to axonal injury.
Main Methods:
- Examined transcriptional control of cell death, ER stress, and regeneration genes following axonal injury in wildtype and Jun-deficient RGCs.
- Assessed the impact of Hrk and Atf3 gene deficiencies on RGC death after axonal injury.
- Analyzed the expression of AP1 family members in response to axonal injury and Jun deficiency.
Main Results:
- Jun deficiency altered the expression of numerous injury-responsive genes, including Atf3, Ddit3, Gadd45α, Hrk, and Sprr1a.
- While Hrk deficiency did not affect RGC death, Atf3 deficiency partially reduced RGC death post-injury.
- Axonal injury induced multiple AP1 family members, with altered expression patterns in Jun-deficient retinas.
Conclusions:
- JUN plays a multifaceted role in regulating the RGC response to axonal injury.
- JUN's regulation of specific genes, like Atf3, influences RGC survival.
- JUN's dimerization partners contribute to its diverse transcriptional targets in neuronal injury.
