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JUN is important for ocular hypertension-induced retinal ganglion cell degeneration.
Cell Death Dis. 2017 07 20; 8(7):e2945.CD

Abstract

Ocular hypertension, a major risk factor for glaucoma, is thought to trigger glaucomatous neurodegeneration through injury to retinal ganglion cell (RGC) axons. The molecular signaling pathway leading from ocular hypertension to RGC degeneration, however, is not well defined. JNK signaling, a component of the mitogen-activated protein kinase (MAPK) family, and its canonical target, the transcription factor JUN, have been shown to regulate neurodegeneration in many different systems. JUN is expressed after glaucoma-relevant injuries and Jun deficiency protects RGCs after mechanical injury to the optic nerve. Here, we tested the importance of JNK-JUN signaling for RGC death after ocular hypertensive axonal injury in an age-related, mouse model of ocular hypertension. Immunohistochemistry was performed to evaluate JUN expression in ocular hypertensive DBA/2J mice. JUN was expressed in a temporal and spatial pattern consistent with a role in glaucomatous injury. To determine the importance of JUN in ocular hypertension-induced RGC death, a floxed allele of Jun and a retinal expressed cre recombinase (Six3-cre) were backcrossed onto the DBA/2J background. Intraocular pressure (IOP) and gross morphology of the retina and optic nerve head were assessed to determine whether removing Jun from the developing retina altered IOP elevation or retinal development. Jun deficiency in the retina did not alter DBA/2J IOP elevation or retinal development. Optic nerves and retinas were assessed at ages known to have glaucomatous damage in DBA/2J mice. Jun deficiency protected RGC somas from ocular hypertensive injury, but did not protect RGC axons from glaucomatous neurodegeneration. Jun is a major regulator of RGC somal degeneration after glaucomatous ocular hypertensive injury. These results suggest in glaucomatous neurodegeneration, JNK-JUN signaling has a major role as a pro-death signaling pathway between axonal injury and somal degeneration.

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Authors+Show Affiliations

Syc-Mazurek SB
Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Neuroscience Graduate Program, University of Rochester Medical Center, Rochester, NY 14642, USA.
Fernandes KA
Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
Libby RT
Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA. The Center for Visual Sciences, University of Rochester Medical Center, Rochester, NY 14642, USA.

MeSH

AnimalsAxonsDisease Models, AnimalGene Expression RegulationMAP Kinase Kinase 4MiceMice, KnockoutOcular HypertensionProto-Oncogene Proteins c-junRetinal Ganglion CellsSignal Transduction

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28726785

Citation

Syc-Mazurek, Stephanie B., et al. "JUN Is Important for Ocular Hypertension-induced Retinal Ganglion Cell Degeneration." Cell Death & Disease, vol. 8, no. 7, 2017, pp. e2945.
Syc-Mazurek SB, Fernandes KA, Libby RT. JUN is important for ocular hypertension-induced retinal ganglion cell degeneration. Cell Death Dis. 2017;8(7):e2945.
Syc-Mazurek, S. B., Fernandes, K. A., & Libby, R. T. (2017). JUN is important for ocular hypertension-induced retinal ganglion cell degeneration. Cell Death & Disease, 8(7), e2945. https://doi.org/10.1038/cddis.2017.338
Syc-Mazurek SB, Fernandes KA, Libby RT. JUN Is Important for Ocular Hypertension-induced Retinal Ganglion Cell Degeneration. Cell Death Dis. 2017 07 20;8(7):e2945. PubMed PMID: 28726785.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - JUN is important for ocular hypertension-induced retinal ganglion cell degeneration. AU - Syc-Mazurek,Stephanie B, AU - Fernandes,Kimberly A, AU - Libby,Richard T, Y1 - 2017/07/20/ PY - 2017/04/06/received PY - 2017/06/06/revised PY - 2017/06/12/accepted PY - 2017/7/21/entrez PY - 2017/7/21/pubmed PY - 2018/4/6/medline SP - e2945 EP - e2945 JF - Cell death & disease JO - Cell Death Dis VL - 8 IS - 7 N2 - Ocular hypertension, a major risk factor for glaucoma, is thought to trigger glaucomatous neurodegeneration through injury to retinal ganglion cell (RGC) axons. The molecular signaling pathway leading from ocular hypertension to RGC degeneration, however, is not well defined. JNK signaling, a component of the mitogen-activated protein kinase (MAPK) family, and its canonical target, the transcription factor JUN, have been shown to regulate neurodegeneration in many different systems. JUN is expressed after glaucoma-relevant injuries and Jun deficiency protects RGCs after mechanical injury to the optic nerve. Here, we tested the importance of JNK-JUN signaling for RGC death after ocular hypertensive axonal injury in an age-related, mouse model of ocular hypertension. Immunohistochemistry was performed to evaluate JUN expression in ocular hypertensive DBA/2J mice. JUN was expressed in a temporal and spatial pattern consistent with a role in glaucomatous injury. To determine the importance of JUN in ocular hypertension-induced RGC death, a floxed allele of Jun and a retinal expressed cre recombinase (Six3-cre) were backcrossed onto the DBA/2J background. Intraocular pressure (IOP) and gross morphology of the retina and optic nerve head were assessed to determine whether removing Jun from the developing retina altered IOP elevation or retinal development. Jun deficiency in the retina did not alter DBA/2J IOP elevation or retinal development. Optic nerves and retinas were assessed at ages known to have glaucomatous damage in DBA/2J mice. Jun deficiency protected RGC somas from ocular hypertensive injury, but did not protect RGC axons from glaucomatous neurodegeneration. Jun is a major regulator of RGC somal degeneration after glaucomatous ocular hypertensive injury. These results suggest in glaucomatous neurodegeneration, JNK-JUN signaling has a major role as a pro-death signaling pathway between axonal injury and somal degeneration. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/28726785/JUN_is_important_for_ocular_hypertension_induced_retinal_ganglion_cell_degeneration_ L2 - https://doi.org/10.1038/cddis.2017.338 DB - PRIME DP - Unbound Medicine ER -