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

Retinal ganglion cell (RGC) death is a critical component of glaucoma pathology. The degenerative signaling pathways that lead to RGC death in glaucoma are incompletely defined. Recently, the transcription factors JUN and DDIT3 were identified as critical hubs regulating RGC somal loss after mechanical axonal injury. However, their position within the degenerative cascade remains unclear. One possibility is that JUN and DDIT3 activity in the soma initiates signaling events that trigger axonal degeneration. Alternatively, JUN and DDIT3 may function downstream of the primary insult, acting specifically to mediate somal degeneration without influencing axonal pathology. Disentangling these possibilities is critical for understanding the compartment-specific mechanisms of RGC degeneration in glaucoma. The MAP2Ks MKK4 and MKK7 control JNK and JUN activity and can indirectly activate DDIT3. Furthermore, MKK4 and MKK7 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 injuries; including ocular hypertension in aged DBA/2J mice and after mechanical axonal injury (controlled optic nerve crush, CONC) in C57BL/6J mice. Ddit3 and Jun deletion did not prevent RGC axonal degeneration in DBA/2J mice but prevented nearly all somal loss. Despite robust somal survival, Ddit3 and Jun deletion did not prevent RGC somal shrinkage or pattern electroretinography (PERG) amplitude decline in DBA/2J mice or after CONC in C57BL/6J mice. In contrast, Mkk4 and Mkk7 deletion from C57BL/6J mice significantly lessened RGC soma and axon degeneration while preserving PERG amplitude and soma size after CONC. In summary, activation of MKK4 and MKK7 may be an inciting mechanism governing RGC somal and axonal degeneration after glaucoma-relevant axonal injury.