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bioRxiv · 10.1101/2024.09.27.614559

MKK4 and MKK7 control degeneration of retinal ganglion cell somas and axons after glaucoma-relevant injury.

Marola, O. J.·Syc-Mazurek, S. B.·Yablonski, S. E. R.·Shrager, P. G.·John, S. W. M.·Libby, R. T.
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Abstract

Glaucoma is characterized by programmed cell death of retinal ganglion cells (RGCs) after axonal injury. Several studies have shown the cell-intrinsic drivers of RGC degeneration act in a compartment-specific manor. Recently, the transcription factors JUN and DDIT3 were identified as critical hubs regulating RGC somal loss after mechanical axonal injury. It is possible somal DDIT3/JUN activity initiates axonal degeneration mechanisms in glaucoma. Alternatively, DDIT3/JUN may act downstream of inciting degenerative mechanisms and only drive RGC somal loss. The MAP2Ks MKK4 and MKK7 control all JNK/JUN activity and can indirectly activate DDIT3. Furthermore, MKK4/7 have been shown to drive RGC axonal degeneration after mechanical axonal injury. The present work investigated whether JUN and DDIT3, or their upstream activators MKK4 and MKK7, control degeneration of RGC axons and somas after glaucoma-relevant injury. Ddit3/Jun deletion did not prevent axonal degeneration in ocular hypertensive DBA/2J mice but prevented nearly all RGC somal loss. Despite robust somal survival, Ddit3/Jun deletion did not preserve RGC somal viability (as assessed by PERG decline and soma shrinkage) in DBA/2J mice or after glaucoma-relevant mechanical axonal injury. In contrast, Mkk4/7 deletion significantly lessened degeneration of RGC somas and axons, and preserved somal function and size after axonal injury. In summary, activation of MKK4 and MKK7 appears to be the inciting mechanism governing death of the entire RGC after glaucoma-relevant injury; driving death of the RGC soma (likely through activation of DDIT3 and JUN), decline in somal viability, and axonal degeneration via DDIT3/JUN-independent mechanisms.

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Marola, O. J., Syc-Mazurek, S. B., Yablonski, S. E. R., Shrager, P. G., John, S. W. M., Libby, R. T.. 2024-09-28. MKK4 and MKK7 control degeneration of retinal ganglion cell somas and axons after glaucoma-relevant injury.. https://doi.org/10.1101/2024.09.27.614559

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