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Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death.
Cell Death Dis. 2018 10 26; 9(11):1095.CD

Abstract

The mitogen-activated protein kinase (MAPK) pathway has been shown to be involved in both neurodevelopment and neurodegeneration. c-Jun N-terminal kinase (JNK), a MAPK important in retinal development and after optic nerve crush injury, is regulated by two upstream kinases: MKK4 and MKK7. The specific requirements of MKK4 and MKK7 in retinal development and retinal ganglion cell (RGC) death after axonal injury, however, are currently undefined. Optic nerve injury is an important insult in many neurologic conditions including traumatic, ischemic, inflammatory, and glaucomatous optic neuropathies. Mice deficient in Mkk4, Mkk7, and both Mkk4 and Mkk7 were generated. Immunohistochemistry was used to study the distribution and structure of retinal cell types and to assess RGC survival after optic nerve injury (mechanical controlled optic nerve crush (CONC)). Adult Mkk4- and Mkk7-deficient retinas had all retinal cell types, and with the exception of small areas of disrupted photoreceptor lamination in Mkk4-deficient mice, the retinas of both mutants were grossly normal. Deficiency of Mkk4 or Mkk7 reduced JNK signaling in RGCs after axonal injury and resulted in a significantly greater percentage of surviving RGCs 35 days after CONC as compared to wild-type controls (Mkk4: 51.5%, Mkk7: 29.1%, WT: 15.2%; p < 0.001). Combined deficiency of Mkk4 and Mkk7 caused failure of optic nerve formation, irregular retinal axonal trajectories, disruption of retinal lamination, clumping of RGC bodies, and dendritic fasciculation of dopaminergic amacrine cells. These results suggest that MKK4 and MKK7 may serve redundant and unique roles in molecular signaling important for retinal development and injury response following axonal insult.

Authors+Show Affiliations

Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, USA. Neuroscience Graduate Program, University of Rochester Medical Center, Rochester, NY, USA.Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, USA. Neuroscience Graduate Program, University of Rochester Medical Center, Rochester, NY, USA.Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, USA.Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, USA.Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, USA. richard_libby@urmc.rochester.edu. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA. richard_libby@urmc.rochester.edu. The Center for Visual Sciences, University of Rochester, Rochester, NY, USA. richard_libby@urmc.rochester.edu.

Pub Type(s)

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

Language

eng

PubMed ID

30367030

Citation

Syc-Mazurek, Stephanie B., et al. "Mkk4 and Mkk7 Are Important for Retinal Development and Axonal Injury-induced Retinal Ganglion Cell Death." Cell Death & Disease, vol. 9, no. 11, 2018, p. 1095.
Syc-Mazurek SB, Rausch RL, Fernandes KA, et al. Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death. Cell Death Dis. 2018;9(11):1095.
Syc-Mazurek, S. B., Rausch, R. L., Fernandes, K. A., Wilson, M. P., & Libby, R. T. (2018). Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death. Cell Death & Disease, 9(11), 1095. https://doi.org/10.1038/s41419-018-1079-7
Syc-Mazurek SB, et al. Mkk4 and Mkk7 Are Important for Retinal Development and Axonal Injury-induced Retinal Ganglion Cell Death. Cell Death Dis. 2018 10 26;9(11):1095. PubMed PMID: 30367030.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death. AU - Syc-Mazurek,Stephanie B, AU - Rausch,Rebecca L, AU - Fernandes,Kimberly A, AU - Wilson,Michael P, AU - Libby,Richard T, Y1 - 2018/10/26/ PY - 2018/03/01/received PY - 2018/09/10/accepted PY - 2018/08/28/revised PY - 2018/10/28/entrez PY - 2018/10/28/pubmed PY - 2019/12/18/medline SP - 1095 EP - 1095 JF - Cell death & disease JO - Cell Death Dis VL - 9 IS - 11 N2 - The mitogen-activated protein kinase (MAPK) pathway has been shown to be involved in both neurodevelopment and neurodegeneration. c-Jun N-terminal kinase (JNK), a MAPK important in retinal development and after optic nerve crush injury, is regulated by two upstream kinases: MKK4 and MKK7. The specific requirements of MKK4 and MKK7 in retinal development and retinal ganglion cell (RGC) death after axonal injury, however, are currently undefined. Optic nerve injury is an important insult in many neurologic conditions including traumatic, ischemic, inflammatory, and glaucomatous optic neuropathies. Mice deficient in Mkk4, Mkk7, and both Mkk4 and Mkk7 were generated. Immunohistochemistry was used to study the distribution and structure of retinal cell types and to assess RGC survival after optic nerve injury (mechanical controlled optic nerve crush (CONC)). Adult Mkk4- and Mkk7-deficient retinas had all retinal cell types, and with the exception of small areas of disrupted photoreceptor lamination in Mkk4-deficient mice, the retinas of both mutants were grossly normal. Deficiency of Mkk4 or Mkk7 reduced JNK signaling in RGCs after axonal injury and resulted in a significantly greater percentage of surviving RGCs 35 days after CONC as compared to wild-type controls (Mkk4: 51.5%, Mkk7: 29.1%, WT: 15.2%; p < 0.001). Combined deficiency of Mkk4 and Mkk7 caused failure of optic nerve formation, irregular retinal axonal trajectories, disruption of retinal lamination, clumping of RGC bodies, and dendritic fasciculation of dopaminergic amacrine cells. These results suggest that MKK4 and MKK7 may serve redundant and unique roles in molecular signaling important for retinal development and injury response following axonal insult. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/30367030/Mkk4_and_Mkk7_are_important_for_retinal_development_and_axonal_injury_induced_retinal_ganglion_cell_death_ L2 - https://doi.org/10.1038/s41419-018-1079-7 DB - PRIME DP - Unbound Medicine ER -