scholarly journals Harnessing Astrocytes and Müller Glial Cells in the Retina for Survival and Regeneration of Retinal Ganglion Cells

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1339
Author(s):  
Hyung-Suk Yoo ◽  
Ushananthini Shanmugalingam ◽  
Patrice D. Smith
Keyword(s):  
Spinal Cord ◽  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Axon Regeneration ◽  
Ganglion Cells ◽  
Reactive Gliosis ◽  
Retinal Ganglion ◽  
Cord Injury ◽  
The Central Nervous System ◽  
Retinal Degenerative Diseases

Astrocytes have been associated with the failure of axon regeneration in the central nervous system (CNS), as it undergoes reactive gliosis in response to damages to the CNS and functions as a chemical and physical barrier to axon regeneration. However, beneficial roles of astrocytes have been extensively studied in the spinal cord over the years, and a growing body of evidence now suggests that inducing astrocytes to become more growth-supportive can promote axon regeneration after spinal cord injury (SCI). In retina, astrocytes and Müller cells are known to undergo reactive gliosis after damage to retina and/or optic nerve and are hypothesized to be either detrimental or beneficial to survival and axon regeneration of retinal ganglion cells (RGCs). Whether they can be induced to become more growth-supportive after retinal and optic nerve injury has yet to be determined. In this review, we pinpoint the potential molecular pathways involved in the induction of growth-supportive astrocytes in the spinal cord and suggest that stimulating the activation of these pathways in the retina could represent a new therapeutic approach to promoting survival and axon regeneration of RGCs in retinal degenerative diseases.

scholarly journals Changes in axonally transported proteins during axon regeneration in toad retinal ganglion cells.

1981 ◽  
Vol 89 (1) ◽  
pp. 86-95 ◽  
Author(s):  
J H Skene ◽  
M Willard
Keyword(s):  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Axon Regeneration ◽  
Ganglion Cells ◽  
Small Subset ◽  
Retinal Ganglion ◽  
Radioactive Label ◽  
Altered Expression ◽  
Growth State ◽  
Mature Neuron

In an effort to understand the regulation of the transition of a mature neuron to the growth, or regenerating, state we have analyzed the composition of the axonally transported proteins in the retinal ganglion cells of the toad Bufo marinus after inducing axon regeneration by crushing the optic nerve. At increasing intervals after axotomy, we labeled the retinal ganglion cells with [35S]methionine and subsequently analyzed the labeled transported polypeptides in the crushed optic nerve by means of one- and two-dimensional electrophoretic techniques. The most significant conclusion from these experiments is that, while the transition from the mature to the regenerating state does not require a gross qualitative alteration in the composition of axonally transported proteins, the relative labeling of a small subset of rapidly transported proteins is altered dramatically (changes of more than 20-fold) and reproducibly (more than 30 animals) by axotomy. One of these growth-associated proteins (GAPs) was soluble in an aqueous buffer, while three were associated with a crude membrane fraction. The labeling of all three of the membrane-associated GAPs increased during the first 8 d after axotomy, and they continued to be labeled for at least 4 wk. The modulation of these proteins after axotomy is consistent with the possibility that they are involve in growth-specific functions and that the altered expression of a small number of genes is a crucial regulatory event in the transition of a mature neuron to a growth state. In addition to these selective changes in rapidly transported proteins, we observed the following more general metabolic correlates of the regeneration process: The total radioactive label associated with the most rapidly transported proteins (groups I and II) increased three to fourfold during the first 8 d after the nerve was crushed, while the total label associated with more slowly moving proteins (group IV) increased about 10-fold during this same period. Among these more slowly transported polypeptides, five were observed whose labeling increased much more than the average. Three of these five polypeptides resemble actin and alpha- and beta-tubulin in their electrophoretic properties.

scholarly journals Knocking out non-muscle myosin II in retinal ganglion cells promotes long-distance optic nerve regeneration

2019 ◽  
Author(s):  
Xue-Wei Wang ◽  
Shu-Guang Yang ◽  
Chi Zhang ◽  
Jin-Jin Ma ◽  
Yingchi Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Axon Regeneration ◽  
Ganglion Cells ◽  
Myosin Ii ◽  
Retinal Ganglion ◽  
Long Distance ◽  
Optic Nerve Regeneration ◽  
Cytoskeletal Dynamics

AbstractIn addition to altered gene expression, pathological cytoskeletal dynamics in the axon are another key intrinsic barrier for axon regeneration in the central nervous system (CNS). Here we showed that knocking out myosin IIA/B in retinal ganglion cells alone either before or after optic nerve crush induced marked and sustained optic nerve regeneration. Combined Lin28 overexpression and myosin IIA/B knockout led to synergistic promoting effect and long-distance axon regeneration. Immunostaining, RNA-seq and western blot analyses revealed that myosin II deletion did not affect known axon regeneration signaling pathways or the expression of regeneration associated genes. Instead, it abolished the retraction bulb formation and significantly enhanced the axon extension efficiency. The study provided clear evidence that directly targeting neuronal cytoskeleton was sufficient to induce strong CNS axon regeneration, and combining gene expression in the soma and modified cytoskeletal dynamics in the axon was a promising approach for long-distance CNS axon regeneration.

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 Photoreceptive retinal ganglion cells control the information rate of the optic nerve

2018 ◽  
Vol 115 (50) ◽  
pp. E11817-E11826 ◽  
Author(s):  
Nina Milosavljevic ◽  
Riccardo Storchi ◽  
Cyril G. Eleftheriou ◽  
Andrea Colins ◽  
Rasmus S. Petersen ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Information Flow ◽  
Information Transfer ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Ambient Light ◽  
Visual Responses ◽  
Light Irradiance ◽  
The Brain

Information transfer in the brain relies upon energetically expensive spiking activity of neurons. Rates of information flow should therefore be carefully optimized, but mechanisms to control this parameter are poorly understood. We address this deficit in the visual system, where ambient light (irradiance) is predictive of the amount of information reaching the eye and ask whether a neural measure of irradiance can therefore be used to proactively control information flow along the optic nerve. We first show that firing rates for the retina’s output neurons [retinal ganglion cells (RGCs)] scale with irradiance and are positively correlated with rates of information and the gain of visual responses. Irradiance modulates firing in the absence of any other visual signal confirming that this is a genuine response to changing ambient light. Irradiance-driven changes in firing are observed across the population of RGCs (including in both ON and OFF units) but are disrupted in mice lacking melanopsin [the photopigment of irradiance-coding intrinsically photosensitive RGCs (ipRGCs)] and can be induced under steady light exposure by chemogenetic activation of ipRGCs. Artificially elevating firing by chemogenetic excitation of ipRGCs is sufficient to increase information flow by increasing the gain of visual responses, indicating that enhanced firing is a cause of increased information transfer at higher irradiance. Our results establish a retinal circuitry driving changes in RGC firing as an active response to alterations in ambient light to adjust the amount of visual information transmitted to the brain.

scholarly journals Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma

2007 ◽  
Vol 179 (7) ◽  
pp. 1523-1537 ◽  
Author(s):  
Gareth R. Howell ◽  
Richard T. Libby ◽  
Tatjana C. Jakobs ◽  
Richard S. Smith ◽  
F. Campbell Phalan ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mouse Model ◽  
Retinal Ganglion Cells ◽  
Strong Evidence ◽  
Ganglion Cells ◽  
Lamina Cribrosa ◽  
Retinal Ganglion ◽  
Rich Region ◽  
Pattern Electroretinography ◽  
Axon Damage

Here, we use a mouse model (DBA/2J) to readdress the location of insult(s) to retinal ganglion cells (RGCs) in glaucoma. We localize an early sign of axon damage to an astrocyte-rich region of the optic nerve just posterior to the retina, analogous to the lamina cribrosa. In this region, a network of astrocytes associates intimately with RGC axons. Using BAX-deficient DBA/2J mice, which retain all of their RGCs, we provide experimental evidence for an insult within or very close to the lamina in the optic nerve. We show that proximal axon segments attached to their cell bodies survive to the proximity of the lamina. In contrast, axon segments in the lamina and behind the eye degenerate. Finally, the Wlds allele, which is known to protect against insults to axons, strongly protects against DBA/2J glaucoma and preserves RGC activity as measured by pattern electroretinography. These experiments provide strong evidence for a local insult to axons in the optic nerve.

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