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 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.

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Human mesenchymal stem cell therapy promotes retinal ganglion cell survival and target reconnection after optic nerve crush in adult rats

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02130-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Almir Jordão da Silva-Junior ◽

Louise Alessandra Mesentier-Louro ◽

Gabriel Nascimento-dos-Santos ◽

Leandro Coelho Teixeira-Pinheiro ◽

Juliana F. Vasques ◽

...

Keyword(s):

Optic Nerve ◽

Cell Therapy ◽

Nerve Injury ◽

Vision Loss ◽

Visual Signals ◽

Human Mscs ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Optic Nerve Injury ◽

Nerve Crush

Abstract Background Optic-nerve injury results in impaired transmission of visual signals to central targets and leads to the death of retinal ganglion cells (RGCs) and irreversible vision loss. Therapies with mesenchymal stem cells (MSCs) from different sources have been used experimentally to increase survival and regeneration of RGCs. Methods We investigated the efficacy of human umbilical Wharton’s jelly-derived MSCs (hWJ-MSCs) and their extracellular vesicles (EVs) in a rat model of optic nerve crush. Results hWJ-MSCs had a sustained neuroprotective effect on RGCs for 14, 60, and 120 days after optic nerve crush. The same effect was obtained using serum-deprived hWJ-MSCs, whereas transplantation of EVs obtained from those cells was ineffective. Treatment with hWJ-MSCs also promoted axonal regeneration along the optic nerve and reinnervation of visual targets 120 days after crush. Conclusions The observations showed that this treatment with human-derived MSCs promoted sustained neuroprotection and regeneration of RGCs after optic nerve injury. These findings highlight the possibility to use cell therapy to preserve neurons and to promote axon regeneration, using a reliable source of human MSCs.

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In vivo effects of single or combined topical neuroprotective and regenerative agents on degeneration of retinal ganglion cells in rat optic nerve crush model

Scientific Reports ◽

10.1038/s41598-018-36473-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Yuta Kitamura ◽

Guzel Bikbova ◽

Takayuki Baba ◽

Shuichi Yamamoto ◽

Toshiyuki Oshitari

Keyword(s):

Optic Nerve ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Nerve Crush ◽

In Vivo Effects

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Longitudinal In Vivo Imaging of Retinal Ganglion Cells and Retinal Thickness Changes Following Optic Nerve Injury in Mice

PLoS ONE ◽

10.1371/journal.pone.0040352 ◽

2012 ◽

Vol 7 (6) ◽

pp. e40352 ◽

Cited By ~ 35

Author(s):

Balwantray C. Chauhan ◽

Kelly T. Stevens ◽

Julie M. Levesque ◽

Andrea C. Nuschke ◽

Glen P. Sharpe ◽

...

Keyword(s):

Optic Nerve ◽

Nerve Injury ◽

Retinal Ganglion Cells ◽

In Vivo Imaging ◽

Ganglion Cells ◽

Retinal Thickness ◽

Retinal Ganglion ◽

Optic Nerve Injury

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Mesoscopic cortical network reorganization during recovery of partial optic nerve injury in GCaMP6s mice

10.1101/2020.06.28.173799 ◽

2020 ◽

Author(s):

Marianne Groleau ◽

Mojtaba Nazari-Ahangarkolaee ◽

Matthieu P. Vanni ◽

Jacqueline L. Higgins ◽

Anne-Sophie Vézina Bédard ◽

...

Keyword(s):

Visual Acuity ◽

Optic Nerve ◽

Nerve Injury ◽

Cortical Plasticity ◽

Ganglion Cells ◽

Wide Field ◽

Optic Nerve Injury ◽

Nerve Crush ◽

Correlated Activity

AbstractAs the residual vision following a traumatic optic nerve injury can spontaneously recover over time, we explored the plasticity of cortical networks during the early post-optic nerve crush (ONC) phase. Using in vivo wide-field calcium imaging on awake Thy1-GCaMP6s mice, we characterized resting state and evoked cortical activity before, during, and 30 days after ONC. The recovery of monocular visual acuity and depth perception was evaluated at the same time points. Cortical responses to an LED flash decreased in the contralateral hemisphere in the primary visual cortex and in the secondary visual areas following the ONC, but was partially rescued between 3 and 5 days post-ONC, remaining stable thereafter. The connectivity between visual and non-visual regions was disorganized after the crush, as shown by a decorrelation, but correlated activity was restored 30 days after the injury. The number of surviving retinal ganglion cells dramatically dropped and remained low. At the behavioral level, the ONC resulted in visual acuity loss on the injured side and an increase in visual acuity with the non-injured eye. In conclusion, our results show a reorganization of connectivity between visual and associative cortical areas after an ONC, which is indicative of spontaneous cortical plasticity.

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Citrus Naringenin Increases Neuron Survival in Optic Nerve Crush Injury Model by Inhibiting JNK-JUN Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms23010385 ◽

2021 ◽

Vol 23 (1) ◽

pp. 385

Author(s):

Jie Chen ◽

Hui Li ◽

Changming Yang ◽

Yinjia He ◽

Tatsuo Arai ◽

...

Keyword(s):

Optic Nerve ◽

Nerve Injury ◽

Ganglion Cells ◽

Crush Injury ◽

Optic Nerve Crush ◽

Nerve Crush ◽

Injury Model ◽

Nerve Crush Injury

Traumatic nerve injury activates cell stress pathways, resulting in neuronal death and loss of vital neural functions. To date, there are no available neuroprotectants for the treatment of traumatic neural injuries. Here, we studied three important flavanones of citrus components, in vitro and in vivo, to reveal their roles in inhibiting the JNK (c-Jun N-terminal kinase)-JUN pathway and their neuroprotective effects in the optic nerve crush injury model, a kind of traumatic nerve injury in the central nervous system. Results showed that both neural injury in vivo and cell stress in vitro activated the JNK-JUN pathway and increased JUN phosphorylation. We also demonstrated that naringenin treatment completely inhibited stress-induced JUN phosphorylation in cultured cells, whereas nobiletin and hesperidin only partially inhibited JUN phosphorylation. Neuroprotection studies in optic nerve crush injury mouse models revealed that naringenin treatment increased the survival of retinal ganglion cells after traumatic optic nerve injury, while the other two components had no neuroprotective effect. The neuroprotection effect of naringenin was due to the inhibition of JUN phosphorylation in crush-injured retinal ganglion cells. Therefore, the citrus component naringenin provides neuroprotection through the inhibition of the JNK-JUN pathway by inhibiting JUN phosphorylation, indicating the potential application of citrus chemical components in the clinical therapy of traumatic optic nerve injuries.

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Longitudinal In Vivo Changes in Retinal Ganglion Cell Dendritic Morphology After Acute and Chronic Optic Nerve Injury

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.62.9.5 ◽

2021 ◽

Vol 62 (9) ◽

pp. 5

Author(s):

Delaney C. M. Henderson ◽

Jayme R. Vianna ◽

John Gobran ◽

Johnny Di Pierdomenico ◽

Michele L. Hooper ◽

...

Keyword(s):

Optic Nerve ◽

Ganglion Cell ◽

Nerve Injury ◽

Retinal Ganglion Cell ◽

Dendritic Morphology ◽

Retinal Ganglion ◽

Optic Nerve Injury

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Mesoscopic cortical network reorganization during recovery of optic nerve injury in GCaMP6s mice

Scientific Reports ◽

10.1038/s41598-020-78491-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Marianne Groleau ◽

Mojtaba Nazari-Ahangarkolaee ◽

Matthieu P. Vanni ◽

Jacqueline L. Higgins ◽

Anne-Sophie Vézina Bédard ◽

...

Keyword(s):

Visual Acuity ◽

Optic Nerve ◽

Nerve Injury ◽

Cortical Plasticity ◽

Ganglion Cells ◽

Wide Field ◽

Optic Nerve Injury ◽

Nerve Crush ◽

Correlated Activity

AbstractAs the residual vision following a traumatic optic nerve injury can spontaneously recover over time, we explored the spontaneous plasticity of cortical networks during the early post-optic nerve crush (ONC) phase. Using in vivo wide-field calcium imaging on awake Thy1-GCaMP6s mice, we characterized resting state and evoked cortical activity before, during, and 31 days after ONC. The recovery of monocular visual acuity and depth perception was evaluated in parallel. Cortical responses to an LED flash decreased in the contralateral hemisphere in the primary visual cortex and in the secondary visual areas following the ONC, but was partially rescued between 3 and 5 days post-ONC, remaining stable thereafter. The connectivity between visual and non-visual regions was disorganized after the crush, as shown by a decorrelation, but correlated activity was restored 31 days after the injury. The number of surviving retinal ganglion cells dramatically dropped and remained low. At the behavioral level, the ONC resulted in visual acuity loss on the injured side and an increase in visual acuity with the non-injured eye. In conclusion, our results show a reorganization of connectivity between visual and associative cortical areas after an ONC, which is indicative of spontaneous cortical plasticity.

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The Susceptibility of Retinal Ganglion Cells to Optic Nerve Injury is Type Specific

Cells ◽

10.3390/cells9030677 ◽

2020 ◽

Vol 9 (3) ◽

pp. 677 ◽

Cited By ~ 3

Author(s):

Ning Yang ◽

Brent K Young ◽

Ping Wang ◽

Ning Tian

Keyword(s):

Optic Nerve ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Survival Rates ◽

Dependent Manner ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Optic Nerve Injury ◽

Traumatic Optic Neuropathy ◽

Nerve Crush

Retinal ganglion cell (RGC) death occurs in many eye diseases, such as glaucoma and traumatic optic neuropathy (TON). Increasing evidence suggests that the susceptibility of RGCs varies to different diseases in an RGC type-dependent manner. We previously showed that the susceptibility of several genetically identified RGC types to N-methyl-D-aspartate (NMDA) excitotoxicity differs significantly. In this study, we characterize the susceptibility of the same RGC types to optic nerve crush (ONC). We show that the susceptibility of these RGC types to ONC varies significantly, in which BD-RGCs are the most resistant RGC type while W3-RGCs are the most sensitive cells to ONC. We also show that the survival rates of BD-RGCs and J-RGCs after ONC are significantly higher than their survival rates after NMDA excitotoxicity. These results are consistent with the conclusion that the susceptibility of RGCs to ONC varies in an RGC type-dependent manner. Further, the susceptibilities of the same types of RGCs to ONC and NMDA excitotoxicity are significantly different. These are valuable insights for understanding of the selective susceptibility of RGCs to various pathological insults and the development of a strategy to protect RGCs from death in disease conditions.

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