scholarly journals Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

2019 ◽  
Author(s):  
Genea Edwards ◽  
Guy A. Perkins ◽  
Keun-Young Kim ◽  
YeEun Kong ◽  
Yonghoon Lee ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Mitochondrial Fission ◽  
Critical Role ◽  
Metabolic Stress ◽  
Retinal Ganglion ◽  
Mitochondrial Fragmentation ◽  
Akt Phosphorylation ◽  
Anchoring Protein

AbstractImpairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases of CaN and total Drp1 level, as well as a decrease of Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.

Melatonin As a Modulator of Degenerative and Regenerative Signaling Pathways in Injured Retinal Ganglion Cells

2019 ◽  
Vol 25 (28) ◽  
pp. 3057-3073 ◽  
Author(s):  
Kobra B. Juybari ◽  
Azam Hosseinzadeh ◽  
Habib Ghaznavi ◽  
Mahboobeh Kamali ◽  
Ahad Sedaghat ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathways ◽  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Ganglion Cells ◽  
Axon Growth ◽  
Nerve Fibers ◽  
Retinal Ganglion

Optic neuropathies refer to the dysfunction or degeneration of optic nerve fibers caused by any reasons including ischemia, inflammation, trauma, tumor, mitochondrial dysfunction, toxins, nutritional deficiency, inheritance, etc. Post-mitotic CNS neurons, including retinal ganglion cells (RGCs) intrinsically have a limited capacity for axon growth after either trauma or disease, leading to irreversible vision loss. In recent years, an increasing number of laboratory evidence has evaluated optic nerve injuries, focusing on molecular signaling pathways involved in RGC death. Trophic factor deprivation (TFD), inflammation, oxidative stress, mitochondrial dysfunction, glutamate-induced excitotoxicity, ischemia, hypoxia, etc. have been recognized as important molecular mechanisms leading to RGC apoptosis. Understanding these obstacles provides a better view to find out new strategies against retinal cell damage. Melatonin, as a wide-spectrum antioxidant and powerful freeradical scavenger, has the ability to protect RGCs or other cells against a variety of deleterious conditions such as oxidative/nitrosative stress, hypoxia/ischemia, inflammatory processes, and apoptosis. In this review, we primarily highlight the molecular regenerative and degenerative mechanisms involved in RGC survival/death and then summarize the possible protective effects of melatonin in the process of RGC death in some ocular diseases including optic neuropathies. Based on the information provided in this review, melatonin may act as a promising agent to reduce RGC death in various retinal pathologic conditions.

scholarly journals Capacity of Retinal Ganglion Cells Derived from Human Induced Pluripotent Stem Cells to Suppress T-Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 7831
Author(s):  
Ayaka Edo ◽  
Sunao Sugita ◽  
Yoko Futatsugi ◽  
Junki Sho ◽  
Akishi Onishi ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Induced Pluripotent Stem Cells ◽  
Retinal Ganglion Cells ◽  
Pluripotent Stem Cells ◽  
Transforming Growth Factor ◽  
Ganglion Cells ◽  
Critical Role ◽  
Retinal Ganglion ◽  
Induced Pluripotent

Retinal ganglion cells (RGCs) are impaired in patients such as those with glaucoma and optic neuritis, resulting in permanent vision loss. To restore visual function, development of RGC transplantation therapy is now underway. Induced pluripotent stem cells (iPSCs) are an important source of RGCs for human allogeneic transplantation. We therefore analyzed the immunological characteristics of iPSC-derived RGCs (iPSC-RGCs) to evaluate the possibility of rejection after RGC transplantation. We first assessed the expression of human leukocyte antigen (HLA) molecules on iPSC-RGCs using immunostaining, and then evaluated the effects of iPSC-RGCs to activate lymphocytes using the mixed lymphocyte reaction (MLR) and iPSC-RGC co-cultures. We observed low expression of HLA class I and no expression of HLA class II molecules on iPSC-RGCs. We also found that iPSC-RGCs strongly suppressed various inflammatory immune cells including activated T-cells in the MLR assay and that transforming growth factor-β2 produced by iPSC-RGCs played a critical role in suppression of inflammatory cells in vitro. Our data suggest that iPSC-RGCs have low immunogenicity, and immunosuppressive capacity on lymphocytes. Our study will contribute to predicting immune attacks after RGC transplantation.

scholarly journals Tbr2-expressing retinal ganglion cells are ipRGCs

2020 ◽  
Author(s):  
Chai-An Mao ◽  
Ching-Kang Chen ◽  
Takae Kiyama ◽  
Nicole Weber ◽  
Christopher M. Whitaker ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Amacrine Cells ◽  
Primary Component ◽  
Retinal Ganglion ◽  
Retinal Neurons ◽  
T Box ◽  
Retinofugal Projections ◽  
A Minor

AbstractThe mammalian retina contains more than 40 retinal ganglion cell (RGC) subtypes based on their unique morphologies, functions, and molecular profiles. Among them, intrinsically photosensitive RGCs (ipRGCs) are the first specified RGC type that emerged from a common pool of retinal progenitor cells. Previous work has shown that T-box transcription factor T-brain 2 (Tbr2) is essential for the formation and maintenance of ipRGCs, and Tbr2-expressing RGCs activate Opn4 expression upon native ipRGC loss, suggesting that Tbr2+ RGCs can serve as a reservoir for ipRGCs. However, the identity of Tbr2+ RGCs has not been fully vetted, and the developmental and molecular mechanisms underlying the formation of native and reservoir ipRGCs remain unclear. Here, we showed that Tbr2-expressing retinal neurons include RGCs and GABAergic displaced amacrine cells (dACs). Using genetic sparse labeling, we demonstrated that the majority of Tbr2+ RGCs are intrinsically photosensitive and morphologically indistinguishable from known ipRGC types and have identical retinofugal projections. Additionally, we found a minor fraction of Pou4f1-expressing Tbr2+ RGCs marks a unique OFF RGC subtype. Most of the Tbr2+ RGCs can be ablated by anti-melanopsin-SAP toxin in adult retinas, supporting that Tbr2+ RGCs contain reservoir ipRGCs that express melanopsin at varying levels. When Tbr2 is deleted in adult retinas, Opn4 expression is diminished followed by the death of Tbr2-deficient cells, suggesting that Tbr2 is essential for both Opn4 expression and ipRGC survival. Finally, Tbr2 extensively occupies multiple T-elements in the Opn4 locus, indicating a direct regulatory role for Tbr2 on Opn4 transcription.Significance statementMelanopsin/Opn4-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) play fundamental roles in non-image forming vision. Previously we identified Tbr2 as the key transcription regulator for the development and maintenance of ipRGCs. To reveal the full identity of Tbr2-expressing retinal neurons and how Tbr2 acts, we generated a novel mouse line to genetically label and study Tbr2-expressing cells. Our in-depth characterizations firmly established that most Tbr2+ RGCs are indeed ipRGCs and that Tbr2 regulates Opn4 transcription, thus place Tbr2-Opn4 transcription regulatory hierarchy as the primary component in the development and maintenance of the non-image forming visual system.

scholarly journals Molecular studies into cell biological role of Copine-4 in Retinal Ganglion Cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0255860
Author(s):  
Manvi Goel ◽  
Angel M. Aponte ◽  
Graeme Wistow ◽  
Tudor C. Badea
Keyword(s):  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Mass Spectrometry Analysis ◽  
Hek293 Cells ◽  
Retinal Cell ◽  
Interacting Proteins ◽  
Retinal Ganglion ◽  
Over Expression

The molecular mechanisms underlying morphological diversity in retinal cell types are poorly understood. We have previously reported that several members of the Copine family of Ca-dependent membrane adaptors are expressed in Retinal Ganglion Cells and transcriptionally regulated by Brn3 transcription factors. Several Copines are enriched in the retina and their over-expression leads to morphological changes -formation of elongated processes-, reminiscent of neurites, in HEK293 cells. However, the role of Copines in the retina is largely unknown. We now investigate Cpne4, a Copine whose expression is restricted to Retinal Ganglion Cells. Over-expression of Cpne4 in RGCs in vivo led to formation of large varicosities on the dendrites but did not otherwise visibly affect dendrite or axon formation. Protein interactions studies using yeast two hybrid analysis from whole retina cDNA revealed two Cpne4 interacting proteins–Host Cell Factor 1 and Morn2. Mass Spectrometry analysis of retina lysate pulled down using Cpne4 or its vonWillebrand A domain showed 207 interacting proteins. A Gene Ontology analysis of the discovered proteins suggests that Cpne4 is involved in several metabolic and signaling pathways in the retina.

scholarly journals Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Genea Edwards ◽  
Guy A. Perkins ◽  
Keun-Young Kim ◽  
YeEun Kong ◽  
Yonghoon Lee ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Mitochondrial Fission ◽  
Retinal Ganglion

scholarly journals A cell–ECM mechanism for connecting the ipsilateral eye to the brain

2021 ◽  
Vol 118 (42) ◽  
pp. e2104343118
Author(s):  
Jianmin Su ◽  
Ubadah Sabbagh ◽  
Yanping Liang ◽  
Lucie Olejníková ◽  
Karen G. Dixon ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Integrin Receptors ◽  
Recognition Mechanism ◽  
A Cell ◽  
Extracellular Glycoprotein ◽  
The Brain ◽  
Parallel Visual Pathways

Information about features in the visual world is parsed by circuits in the retina and is then transmitted to the brain by distinct subtypes of retinal ganglion cells (RGCs). Axons from RGC subtypes are stratified in retinorecipient brain nuclei, such as the superior colliculus (SC), to provide a segregated relay of parallel and feature-specific visual streams. Here, we sought to identify the molecular mechanisms that direct the stereotyped laminar targeting of these axons. We focused on ipsilateral-projecting subtypes of RGCs (ipsiRGCs) whose axons target a deep SC sublamina. We identified an extracellular glycoprotein, Nephronectin (NPNT), whose expression is restricted to this ipsiRGC-targeted sublamina. SC-derived NPNT and integrin receptors expressed by ipsiRGCs are both required for the targeting of ipsiRGC axons to the deep sublamina of SC. Thus, a cell–extracellular matrix (ECM) recognition mechanism specifies precise laminar targeting of ipsiRGC axons and the assembly of eye-specific parallel visual pathways.

scholarly journals Neurogenesis and Specification of Retinal Ganglion Cells

2020 ◽  
Vol 21 (2) ◽  
pp. 451 ◽  
Author(s):  
Kim Tuyen Nguyen-Ba-Charvet ◽  
Alexandra Rebsam
Keyword(s):  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Cell Types ◽  
Retinal Cell ◽  
Retinal Ganglion ◽  
Intrinsic Factors ◽  
Visual Deficits ◽  
Retinal Neurogenesis ◽  
Cell Niche

Across all species, retinal ganglion cells (RGCs) are the first retinal neurons generated during development, followed by the other retinal cell types. How are retinal progenitor cells (RPCs) able to produce these cell types in a specific and timely order? Here, we will review the different models of retinal neurogenesis proposed over the last decades as well as the extrinsic and intrinsic factors controlling it. We will then focus on the molecular mechanisms, especially the cascade of transcription factors that regulate, more specifically, RGC fate. We will also comment on the recent discovery that the ciliary marginal zone is a new stem cell niche in mice contributing to retinal neurogenesis, especially to the generation of ipsilateral RGCs. Furthermore, RGCs are composed of many different subtypes that are anatomically, physiologically, functionally, and molecularly defined. We will summarize the different classifications of RGC subtypes and will recapitulate the specification of some of them and describe how a genetic disease such as albinism affects neurogenesis, resulting in profound visual deficits.

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