Glaucoma is a neurodegenerative disease characterized by death of retinal ganglion cells (RGCs)?the output neurons of the retina. The present studies investigated the extrinsic and intrinsic signaling pathways that elicit RGC death in the context of glaucoma. There is growing evidence the endothelin (EDN) system, canonically known to regulate vasoconstriction, is an important RGC-extrinsic driver of glaucomatous neurodegeneration. Intravitreal injection of EDN ligands caused RGC death, and EDN-induced RGC death was largely mediated by activation of the transcription factor JUN?consistent with RGC death after other glaucoma-relevant injuries. However, it remained unknown which retinal and/or optic nerve cell types EDN ligand directly affects to elicit RGC death. EDN ligands act upon EDN receptors (EDNRA and EDNRB), which are expressed by several cell types including neurons, macroglia, endothelial cells, and vascular mural cells. We found mural cell-specific deletion of Ednra completely prevented both EDN-induced vasoconstriction and RGC death, suggesting EDN insults RGCs via vasoconstriction. These data indicate a potentially important role of impaired blood flow and vascular dysfunction in the context of glaucoma. In addition to extrinsic signaling, much work has investigated the intrinsic mechanisms of RGC death in the context of glaucoma. Degeneration of each RGC compartment (e.g. dendrites, soma, axon) is governed by distinct molecular mechanisms. Here, we tested the importance of the transcription factors DDIT3 (the apoptotic endoplasmic reticulum stress effector) and JUN (the target of MAPK-JNK signaling) in RGC degeneration after glaucoma-relevant injuries. In DBA/2J mice, which naturally develop glaucoma with age, Ddit3/Jun deletion did not prevent RGC axonal degeneration but provided near-complete protection to RGC somas. Despite robust somal protection, Ddit3/Jun deletion did not preserve RGC electrical function (as assessed by pattern electroretinography, PERG) or prevent dendritic retraction. These data indicate that together, DDIT3 and JUN are critical hubs regulating RGC somal degeneration after glaucoma-relevant injury. However, lack of protection to PERG amplitude, axonal survival, and dendritic arbor integrity suggests these degenerative events are controlled by pathways upstream or independent of JUN and DDIT3 activation. MAPKKs 4 and 7 (MKK4/7) act upstream of both JUN and DDIT3 activation and have been shown to drive axonal degeneration cascades. Therefore, we investigated the role of MKK4/7 in RGC somal, axonal, and dendritic degeneration after optic nerve crush (ONC), an acute glaucoma-relevant axonal injury. After ONC, Mkk4/7 deletion robustly protected both RGC somas and axons. Intriguingly, Mkk4/7 deletion preserved electrical output measured by PERGs and prevented dendritic remodeling. These data demonstrate MKK4 and MKK7 control degeneration of several RGC compartments independently of DDIT3 and JUN after glaucoma-relevant injury, suggesting inhibiting MKK4/7 signaling or signaling events upstream of their activation could be a powerful neuroprotective therapy for glaucomatous neurodegeneration.