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

MKK4 and MKK7 control degeneration of retinal ganglion cell somas and axons after glaucoma-relevant injury. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article MKK4 and MKK7 control degeneration of retinal ganglion cell somas and axons after glaucoma-relevant injury. Olivia Marola, Stephanie Syc-Mazurek, Sarah Yablonski, Peter Shrager, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6805128/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Dec, 2025 Read the published version in Cell Death Discovery → Version 1 posted 7 You are reading this latest preprint version 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 and JUN activity initiates axonal degeneration mechanisms in glaucoma. Alternatively, DDIT3 and JUN may act downstream of inciting degenerative mechanisms and only drive RGC somal loss. The MAP2Ks MKK4 and MKK7 control all 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 injury. Ddit3 and 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 and 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 and Mkk7 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 and JUN-independent mechanisms. Biological sciences/Neuroscience/Cell death in the nervous system Biological sciences/Cell biology/Cell death/Apoptosis Biological sciences/Neuroscience/Diseases of the nervous system/Neurodegeneration JUN DDIT3 (CHOP) MAP2K4 MAP2K7 DBA/2J ocular hypertension optic nerve crush axonal injury axonal degeneration Full Text Additional Declarations There is no conflict of interest Cite Share Download PDF Status: Published Journal Publication published 15 Dec, 2025 Read the published version in Cell Death Discovery → Version 1 posted Editorial decision: revise 14 Jul, 2025 Review # 1 received at journal 08 Jul, 2025 Reviewer # 1 agreed at journal 11 Jun, 2025 Reviewers invited by journal 11 Jun, 2025 Submission checks completed at journal 03 Jun, 2025 Editor assigned by journal 02 Jun, 2025 First submitted to journal 02 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6805128","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":469660613,"identity":"6ef39d75-865c-4e80-9f2c-9fc684373884","order_by":0,"name":"Olivia 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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 and JUN activity initiates axonal degeneration mechanisms in glaucoma. Alternatively, DDIT3 and JUN may act downstream of inciting degenerative mechanisms and only drive RGC somal loss. The MAP2Ks MKK4 and MKK7 control all 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 injury. Ddit3 and 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 and 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 and Mkk7 deletion significantly lessened degeneration of RGC somas and axons, and preserved somal function and size after axonal injury. 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