Subtype-specific response of retinal ganglion cells to optic nerve crush

Daniel, Steffi; Clark, Abbot F.; McDowell, Colleen M

doi:10.1038/s41420-018-0069-y

Cited by 51 publications

(50 citation statements)

References 66 publications

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“…Axon damage induced by injury such as from increased intraocular pressure leads to enhanced RGC excitability that can temporarily delay degeneration (Risner et al, 2018). It has also been reported that intrinsically photosensitive retinal ganglion cells (ipRGCs) are more resistant to insult than other RGC subtypes because of their increased electrical excitability (Li et al, 2006;Daniel et al, 2018). In these examples, increased electrical activity correlates with enhanced neuroprotection, consistent with the enhanced RGC survival with PDE4D3 displacement in vivo.…”

Section: Discussionmentioning

confidence: 73%

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment

Boczek

Cameron

et al. 2019

J. Neurosci.

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cAMP signaling is known to be critical in neuronal survival and axon growth. Increasingly the subcellular compartmentation of cAMP signaling has been appreciated, but outside of dendritic synaptic regulation, few cAMP compartments have been defined in terms of molecular composition or function in neurons. Specificity in cAMP signaling is conferred in large part by A-kinase anchoring proteins (AKAPs) that localize protein kinase A and other signaling enzymes to discrete intracellular compartments. We now reveal that cAMP signaling within a perinuclear neuronal compartment organized by the large multivalent scaffold protein mAKAP␣ promotes neuronal survival and axon growth. mAKAP␣ signalosome function is explored using new molecular tools designed to specifically alter local cAMP levels as studied by live-cell FRET imaging. In addition, enhancement of mAKAP␣-associated cAMP signaling by isoform-specific displacement of bound phosphodiesterase is demonstrated to increase retinal ganglion cell survival in vivo in mice of both sexes following optic nerve crush injury. These findings define a novel neuronal compartment that confers cAMP regulation of neuroprotection and axon growth and that may be therapeutically targeted in disease. Significance StatementcAMP is a second messenger responsible for the regulation of diverse cellular processes including neuronal neurite extension and survival following injury. Signal transduction by cAMP is highly compartmentalized in large part because of the formation of discrete, localized multimolecular signaling complexes by A-kinase anchoring proteins. Although the concept of cAMP compartmentation is well established, the function and identity of these compartments remain poorly understood in neurons. In this study, we provide evidence for a neuronal perinuclear cAMP compartment organized by the scaffold protein mAKAP␣ that is necessary and sufficient for the induction of neurite outgrowth in vitro and for the survival of retinal ganglion cells in vivo following optic nerve injury.

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Section: Discussionmentioning

confidence: 73%

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment

Boczek

Cameron

et al. 2019

J. Neurosci.

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“…Previous studies have used various injury and disease models in different animals to elucidate the loss of specific RGCs subtypes, with results somewhat variable based on the model system or the organism used (Birke et al, 2010;Cui et al, 2015;Daniel et al, 2018;Duan et al, 2015;El-Danaf and Huberman, 2015;Majander et al, 2017;Ou et al, 2016;Puyang et al, 2017;Yucel et al, 2003). Results of the current study demonstrated a high susceptibility for direction selective-RGCs and alpha-RGCs following injury, with their survival significantly decreasing after 7 days post ONC.…”

Section: Discussionmentioning

confidence: 59%

“…In contrast to the high susceptibility of certain RGC subtypes, non-image forming ip-RGCs exhibited differential survival following injury compared to image forming direction selective-and alpha-RGCs in the current study. The preferential survival of ip-RGCs has been observed in other studies which utilized rat and mice injury and disease models, with this subtype in particular demonstrating resilience to insult (Cui et al, 2015;Daniel et al, 2018;Li et al, 2006;Li et al, 2008;Perez de Sevilla Muller et al, 2014;Wang et al, 2018). ip-RGCs are unique in that they have the ability to respond to light using the photopigment, Melanopsin, and play a role in non-image forming functions including circadian rhythms and pupillary reflexes by projecting to the superior colliculus, a non-image forming brain region (Chew et al, 2017;Hannibal et al, 2017;Kelbsch et al, 2016).…”

Section: Discussionmentioning

confidence: 64%

“…More so, recent studies have also suggested a differential susceptibility of RGC subtypes in disease or injury states (Birke et al, 2010;Cui et al, 2015;Daniel et al, 2018;Duan et al, 2015;El-Danaf and Huberman, 2015;Majander et al, 2017;Ou et al, 2016;Puyang et al, 2017;Yucel et al, 2003), providing a new opportunity of targeting specific subtypes for treatments and therapeutics. Efforts of the current study utilized an ONC model in rats to elucidate the degeneration of RGCs following injury.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, studies have demonstrated the identification and subsequent degeneration and death of various RGC subtypes in various injury and disease models, including axotomy, optic nerve crush, and glaucoma models (Birke et al, 2010;Cui et al, 2015;Daniel et al, 2018;Duan et al, 2015;El-Danaf and Huberman, 2015;Majander et al, 2017;Ou et al, 2016;Puyang et al, 2017;Yucel et al, 2003), suggesting subtype specific responses to injury. However, these few studies produced limited conclusions as to how various model systems affect RGCs and more specifically, which RGCs subtypes are highly affected in response to disease and injury.…”

Section: Introductionmentioning

confidence: 99%

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Differential Susceptibility of Rat Retinal Ganglion Cells Following Optic Nerve Crush

Wang

et al. 2018

Preprint

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Retinal ganglion cells (RGCs) are a heterogeneous group of cells, comprised of numerous subpopulations, that work together to send visual information to the brain. In numerous blinding disorders termed optic neuropathies, RGCs are the main cell type affected leading to degeneration of these cells and eventual loss of vision. Previous studies have identified and characterized RGC subtypes in numerous animal systems, with only a handful of studies demonstrating their differential loss in response to disease and injury. Thus, efforts of the current study utilized an optic nerve crush (ONC) model to characterize the loss of RGCs and disease phenotypes associated with this injury. Additionally, the loss of RGC subtypes including direction selective-, alpha-, and ip-RGCs following ONC was explored. Results of this study demonstrated the differential loss of RGC subtypes with a high susceptibility for loss of alpha-and direction selective-RGCs and the preferential survival of ip-RGCs following ONC and allows for the establishment of additional studies focused on mechanisms and loss of these cells in optic neuropathies. Additionally, these results put important emphasis on the development of therapeutics targeted at the loss of specific subtypes as well as cellular replacement following injury and disease.

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Distribution of prototypical primary cilia markers in subtypes of retinal ganglion cells

Kowal

Dhande

Wang

et al. 2022

J of Comparative Neurology

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Loss of retinal ganglion cells (RGCs) underlies several forms of retinal disease including glaucomatous optic neuropathy, a leading cause of irreversible blindness. Several rare genetic disorders associated with cilia dysfunction have retinal degeneration as a clinical hallmark. Much of the focus of ciliopathy associated blindness is on the connecting cilium of photoreceptors; however, RGCs also possess primary cilia. It is unclear what roles RGC cilia play, what proteins and signaling machinery localize to RGC cilia, or how RGC cilia are differentiated across the subtypes of RGCs. To better understand these questions, we assessed the presence or absence of a prototypical cilia marker Arl13b and a widely distributed neuronal cilia marker AC3 in different subtypes of mouse RGCs. Interestingly, not all RGC subtype cilia are the same and there are significant differences even among these standard cilia markers. Alpha-RGCs positive for osteopontin, calretinin, and SMI32 primarily possess AC3-positive cilia. Directionally selective RGCs that are CART positive or Trhr positive localize either Arl13b or AC3, respectively, in cilia. Intrinsically photosensitive RGCs differentially localize Arl13b and AC3based on melanopsin expression. Taken together, we characterized the localization of gold standard cilia markers in different subtypes of RGCs and conclude that cilia within RGC subtypes may be differentially organized. Future studies aimed at understanding RGC cilia function will require a fundamental ability to observe the cilia across subtypes as their signaling protein composition is elucidated. A comprehensive understanding of RGC cilia may reveal opportunities to understanding how their dysfunction leads to retinal degeneration.

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Subtype-specific response of retinal ganglion cells to optic nerve crush

Cited by 51 publications

References 66 publications

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment

Differential Susceptibility of Rat Retinal Ganglion Cells Following Optic Nerve Crush

Distribution of prototypical primary cilia markers in subtypes of retinal ganglion cells

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