MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury.
Loss of retinal ganglion cells (RGCs) in optic neuropathies results in permanent partial or complete blindness. Myocyte enhancer factor 2 (MEF2) transcription factors have been shown to play a pivotal role in neuronal systems, and in particular MEF2A knockout was shown to enhance RGC survival after...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0242884 |
| _version_ | 1811309063543193600 |
|---|---|
| author | Xin Xia Caroline Y Yu Minjuan Bian Catalina B Sun Bogdan Tanasa Kun-Che Chang Dawn M Bruffett Hrishikesh Thakur Sahil H Shah Cara Knasel Evan G Cameron Michael S Kapiloff Jeffrey L Goldberg |
| author_facet | Xin Xia Caroline Y Yu Minjuan Bian Catalina B Sun Bogdan Tanasa Kun-Che Chang Dawn M Bruffett Hrishikesh Thakur Sahil H Shah Cara Knasel Evan G Cameron Michael S Kapiloff Jeffrey L Goldberg |
| author_sort | Xin Xia |
| collection | DOAJ |
| description | Loss of retinal ganglion cells (RGCs) in optic neuropathies results in permanent partial or complete blindness. Myocyte enhancer factor 2 (MEF2) transcription factors have been shown to play a pivotal role in neuronal systems, and in particular MEF2A knockout was shown to enhance RGC survival after optic nerve crush injury. Here we expanded these prior data to study bi-allelic, tri-allelic and heterozygous allele deletion. We observed that deletion of all MEF2A, MEF2C, and MEF2D alleles had no effect on RGC survival during development. Our extended experiments suggest that the majority of the neuroprotective effect was conferred by complete deletion of MEF2A but that MEF2D knockout, although not sufficient to increase RGC survival on its own, increased the positive effect of MEF2A knockout. Conversely, MEF2A over-expression in wildtype mice worsened RGC survival after optic nerve crush. Interestingly, MEF2 transcription factors are regulated by post-translational modification, including by calcineurin-catalyzed dephosphorylation of MEF2A Ser-408 known to increase MEF2A-dependent transactivation in neurons. However, neither phospho-mimetic nor phospho-ablative mutation of MEF2A Ser-408 affected the ability of MEF2A to promote RGC death in vivo after optic nerve injury. Together these findings demonstrate that MEF2 gene expression opposes RGC survival following axon injury in a complex hierarchy, and further support the hypothesis that loss of or interference with MEF2A expression might be beneficial for RGC neuroprotection in diseases such as glaucoma and other optic neuropathies. |
| first_indexed | 2024-04-13T09:35:05Z |
| format | Article |
| id | doaj.art-89aa8b9a176d4afeb696a4458a3febf9 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T09:35:05Z |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-89aa8b9a176d4afeb696a4458a3febf92022-12-22T02:52:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-011512e024288410.1371/journal.pone.0242884MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury.Xin XiaCaroline Y YuMinjuan BianCatalina B SunBogdan TanasaKun-Che ChangDawn M BruffettHrishikesh ThakurSahil H ShahCara KnaselEvan G CameronMichael S KapiloffJeffrey L GoldbergLoss of retinal ganglion cells (RGCs) in optic neuropathies results in permanent partial or complete blindness. Myocyte enhancer factor 2 (MEF2) transcription factors have been shown to play a pivotal role in neuronal systems, and in particular MEF2A knockout was shown to enhance RGC survival after optic nerve crush injury. Here we expanded these prior data to study bi-allelic, tri-allelic and heterozygous allele deletion. We observed that deletion of all MEF2A, MEF2C, and MEF2D alleles had no effect on RGC survival during development. Our extended experiments suggest that the majority of the neuroprotective effect was conferred by complete deletion of MEF2A but that MEF2D knockout, although not sufficient to increase RGC survival on its own, increased the positive effect of MEF2A knockout. Conversely, MEF2A over-expression in wildtype mice worsened RGC survival after optic nerve crush. Interestingly, MEF2 transcription factors are regulated by post-translational modification, including by calcineurin-catalyzed dephosphorylation of MEF2A Ser-408 known to increase MEF2A-dependent transactivation in neurons. However, neither phospho-mimetic nor phospho-ablative mutation of MEF2A Ser-408 affected the ability of MEF2A to promote RGC death in vivo after optic nerve injury. Together these findings demonstrate that MEF2 gene expression opposes RGC survival following axon injury in a complex hierarchy, and further support the hypothesis that loss of or interference with MEF2A expression might be beneficial for RGC neuroprotection in diseases such as glaucoma and other optic neuropathies.https://doi.org/10.1371/journal.pone.0242884 |
| spellingShingle | Xin Xia Caroline Y Yu Minjuan Bian Catalina B Sun Bogdan Tanasa Kun-Che Chang Dawn M Bruffett Hrishikesh Thakur Sahil H Shah Cara Knasel Evan G Cameron Michael S Kapiloff Jeffrey L Goldberg MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury. PLoS ONE |
| title | MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury. |
| title_full | MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury. |
| title_fullStr | MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury. |
| title_full_unstemmed | MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury. |
| title_short | MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury. |
| title_sort | mef2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury |
| url | https://doi.org/10.1371/journal.pone.0242884 |
| work_keys_str_mv | AT xinxia mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT carolineyyu mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT minjuanbian mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT catalinabsun mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT bogdantanasa mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT kunchechang mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT dawnmbruffett mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT hrishikeshthakur mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT sahilhshah mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT caraknasel mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT evangcameron mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT michaelskapiloff mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury AT jeffreylgoldberg mef2transcriptionfactorsdifferentiallycontributetoretinalganglioncelllossafteropticnerveinjury |