The Genomic Response to Retinal Disease and Injury: Evidence for Endothelin Signaling from Photoreceptors to Glia

Rattner, Amir; Nathans, Jeremy

doi:10.1523/jneurosci.0492-05.2005

Cited by 187 publications

(243 citation statements)

References 54 publications

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“…This result suggests a positive feedback loop whereby gp130-mediated cell signaling events in rod cells further strengthen the initial CNTF-dependent Müller cell activation. Our quantitative PCR (qPCR) results show that hCNTF significantly enhances EDN2 mRNA expression, thus supporting the participation of exogenous hCNTF in this positive feed-forward signaling loop between Müller glia and photoreceptors (22,45,46). In addition to promoting EDN2 expression, hCNTF also stimulated expression of BDNF and possibly fibroblast growth factor 2 (FGF2), both of which can act as trophic factors on multiple cell types.…”

Section: Discussionsupporting

confidence: 65%

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CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Rhee¹,

Nusinowitz²,

Chao³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective agent in multiple retinal degeneration animal models. Recently, CNTF has been evaluated in clinical trials for the inherited degenerative disease retinitis pigmentosa (RP) and for dry agerelated macular degeneration (AMD). Despite its potential as a broad-spectrum therapeutic treatment for blinding diseases, the target cells of exogenous CNTF and its mechanism of action remain poorly understood. We have shown previously that constitutive expression of CNTF prevents photoreceptor death but alters the retinal transcriptome and suppresses visual function. Here, we use a lentivirus to deliver the same secreted human CNTF used in clinical trials to a mouse model of RP. We found that low levels of CNTF halt photoreceptor death, improve photoreceptor morphology, and correct opsin mislocalization. However, we did not detect corresponding improvement of retinal function as measured by the electroretinogram. Disruption of the cytokine receptor gp130 gene in Müller glia reduces CNTF-dependent photoreceptor survival and prevents phosphorylation of STAT3 and ERK in Müller glia and the rest of the retina. Targeted deletion of gp130 in rods also demolishes neuroprotection by CNTF and prevents further activation of Müller glia. Moreover, CNTF elevates the expression of LIF and endothelin 2, thus positively promoting Müller and photoreceptor interactions. We propose that exogenous CNTF initially targets Müller glia, and subsequently induces cytokines acting through gp130 in photoreceptors to promote neuronal survival. These results elucidate a cellular mechanism for exogenous CNTF-triggered neuroprotection and provide insight into the complex cellular responses induced by CNTF in diseased retinas.C iliary neurotrophic factor (CNTF) belongs to a small subfamily of cytokines and has long been recognized as a potent neuroprotective molecule in the vertebrate retina (1). Enhancement of photoreceptor survival by CNTF has been demonstrated in multiple animal models of retinal degeneration, ranging from zebrafish to canine (2). Interestingly, CNTF is effective in rescuing retinal degeneration due to various causes, including mutations in genes expressed by photoreceptors or the retinal pigment epithelium (RPE), as well as those induced by strong light, neurotoxins, or antibodies. In addition, CNTF prolongs the survival of retinal ganglion cells (3-5) and promotes axonal growth in optic nerve crush or transection models (6-8). Furthermore, CNTF may affect the physiology and survival of RPE cells (9, 10), which are critical in normal vision and retinal degenerative diseases. Based on its significant and broad neuroprotective effects in damaged retinas, a secreted form of human CNTF delivered from an encapsulated cell device has been tested in clinical trials and approved by the Food and Drug Administration (FDA) to treat retinitis pigmentosa (RP) and geographic atrophy (GA), a subset of age-related macular degeneration (AMD) (11-14). However, despite its clinical signifi...

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Section: Discussionsupporting

confidence: 65%

“…Injured photoreceptor-derived endothelin2 (EDN2) acts on its receptor EDNRb expressed by Müller glia (46). Furthermore, EDN2 can induce Müller glia to produce LIF, which acts as a chief neuroprotective agent in the lightinduced and inherited retinal degeneration models (22,45).…”

Section: Discussionmentioning

confidence: 99%

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Rhee¹,

Nusinowitz²,

Chao³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…A recent study demonstrated up-regulation of endothelin 2 (Edn2) in photoreceptors in response to injury induced by several stimuli including bright light exposure, retinal detachment, and certain genetic retinopathies (27). Surprisingly, we found that Edn2 is the third most dorsally enriched gene in the C57BL/6 retina at P21 (SI Table 9).…”

Section: Discussionmentioning

confidence: 69%

A typology of photoreceptor gene expression patterns in the mouse

Corbo

Myers

Lawrence

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in photoreceptor-enriched genes have been implicated in dozens of human retinal diseases, yet no systematic analysis of rod and cone gene expression patterns has been carried out. In addition, although cone photoreceptor loss accounts for much of the morbidity of retinal disease, relatively few cone-specific genes are known. In this study, we carried out microarray and in situ hybridization analyses of the mouse Neural retina leucine zipper gene (Nrl) mutant, which shows an en masse conversion of rods into cones, to establish a typology of photoreceptor gene expression and to identify novel cone-specific genes. We found a total of 18 new cone-enriched genes, some of which map near uncloned retinal disease loci. Several of these genes have a dorsal-ventral (D-V) pattern of expression similar to that of short-or mediumwavelength opsins. We carried out microarray analysis of dorsal and ventral microdissected WT retina and found additional photoreceptor genes with an asymmetric distribution. Overall, we found that photoreceptor genes fall on an expression spectrum from rod-specific to cone-specific, with many showing varying degrees of rod and cone coexpression. These expression patterns can be reliably predicted from microarray data alone. Our results demonstrate definitive molecular differences between rods and cones that may underlie the physiological differences between these two classes of photoreceptors.blindness ͉ cone photoreceptor ͉ retina ͉ rod photoreceptor

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“…Edn2 expression is highly induced in all tested models of photoreceptor disease or injury and points to early abnormalities of the Nxnl1À/À retina. 15 Stress-activated genes are also induced, such as the crystallins, Gckr linked to metabolic stress and retinol dehydrogenase 9 reflecting possible oxidative stress. We also identified the downregulation of genes of the visual cycle, such as Recoverin (Rcvrn) and Irbp3, in coherence with the delay in dark-adaptation ( Figure 3f).…”

Section: Resultsmentioning

confidence: 99%

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

et al. 2010

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Rod-derived cone viability factor (RdCVF) is a thioredoxin-like protein, which has therapeutic potential for rod-cone dystrophies such as retinitis pigmentosa (RP). Cone loss in rodent models of RP is effectively reduced by RdCVF treatment. In this study, we investigate the physiological role of RdCVF in the retina by analyzing the phenotype of the mouse lacking the RdCVF gene, Nxnl1. Although the mice do not show an obvious developmental defect, an age-related reduction of both cone and rod function and a delay in the dark-adaptation of the retina are recorded by electroretinogram (ERG). This functional change is accompanied by a 17% reduction in cone density and a 20% reduction in thickness of the outer nuclear layer. The transcriptome of the retina reveals early changes in the expression of genes involved in programmed cell death, stress-response and redox-signaling, which is followed by a generalized injury response with increased microglial activation, GFAP, FGF2 and lipid peroxidation levels. Furthermore, cones of the mice lacking Nxnl1 are more sensitive to oxidative stress with a reduction of 65% in the cone flicker ERG amplitude measured under hyperoxic conditions. We show here that the RdCVF gene, in addition to therapeutic properties, has an essential role in photoreceptor maintenance and resistance to retinal oxidative stress.

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The Genomic Response to Retinal Disease and Injury: Evidence for Endothelin Signaling from Photoreceptors to Glia

Cited by 187 publications

References 54 publications

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

A typology of photoreceptor gene expression patterns in the mouse

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

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