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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/89aa8b9a176d4afeb696a4458a3febf9
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spelling	oai:doaj.org-article:89aa8b9a176d4afeb696a4458a3febf92021-12-02T20:11:27ZMEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury.1932-620310.1371/journal.pone.0242884https://doaj.org/article/89aa8b9a176d4afeb696a4458a3febf92020-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0242884https://doaj.org/toc/1932-6203Loss 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.Xin XiaCaroline Y YuMinjuan BianCatalina B SunBogdan TanasaKun-Che ChangDawn M BruffettHrishikesh ThakurSahil H ShahCara KnaselEvan G CameronMichael S KapiloffJeffrey L GoldbergPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 15, Iss 12, p e0242884 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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.
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.
format	article
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
title	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_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_sort	mef2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury.
publisher	Public Library of Science (PLoS)
publishDate	2020
url	https://doaj.org/article/89aa8b9a176d4afeb696a4458a3febf9
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MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury.

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