Induction of STAT3-related genes in fast degenerating cone photoreceptors of cpfl1 mice

Schaeferhoff, Karin; Michalakis, Stylianos; Tanimoto, Naoyuki; Fischer, Manuel; Becirovic, Elvir; Beck, Susanne; Huber, Günter L.; Rieger, Norman; Rieß, Olaf; Wissinger, Bernd; Biel, Martin; Seeliger, M. W.; Bonin, Michael

doi:10.1007/s00018-010-0376-9

Cited by 26 publications

(25 citation statements)

References 44 publications

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“…Cpfl1, a naturally occurring cone degeneration mouse line, is another fast and severe cone degeneration model (26,27). Cpfl1 mice received antithyroid drug (methimazole and sodium perchlorate monohydrate) treatment for 30 d, beginning on P1.…”

Section: Resultsmentioning

confidence: 99%

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Thapa

Morris

et al. 2014

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

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Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunitdeficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotidegated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions.R od and cone photoreceptors degenerate under a variety of pathological conditions, including a wide array of hereditary retinal diseases, such as retinitis pigmentosa, macular degeneration, and cone-rod dystrophies. Defects in a large number of genes are linked to inherited retinal degenerative disorders (www.sph. uth.tmc.edu/RetNet/disease.htm), including those encoding enzymes involved in the recycling of 11-cis retinal in the retinal pigment epithelium (RPE), retinoid isomerase (RPE65), and lecithin retinol acyltransferase (LRAT), and the phototransductionassociated proteins (opsins, subunits of transducin, cGMP phosphodiesterase PDE6, guanylate cyclase, and cyclic nucleotidegated channel). There are currently no treatments for human retinal dystrophies. Despite a high genetic heterogeneity, the degenerating photoreceptors show common cellular disorder features, including oxidative damage (1, 2), endoplasmic reticulum stress (3, 4), and apoptosis (5, 6).Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. The role of TH signaling in retina regarding its regulation of cone opsin expression and patterning has been well documented (7,8). Most mammals possess dichromatic color vision that is mediated by two opsins with peak sensitivities to medium-long ...

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Section: Resultsmentioning

confidence: 99%

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Thapa

Morris

et al. 2014

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

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“…We see induction of GFAP in these mice at P120, consistent with GFAP induction as an early indicator of retinal stress. It is not clear why GFAP induction precedes ONL thinning by so substantial a margin, however a similar phenotype has been observed in models of cone dystrophy [39]. In the cpfl1 mouse model of cone dystrophy (Pde6c mutation), pan-retinal GFAP induction is associated with cone stress/degeneration and occurs prior to ONL thinning [39].…”

Section: Discussionmentioning

confidence: 96%

Increased cone sensitivity to ABCA4 deficiency provides insight into macular vision loss in Stargardt's dystrophy

Conley

Cai

Makkia

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Autosomal recessive Stargardt macular dystrophy is caused by mutations in the photoreceptor disc rim protein ABCA4/ABCR. Key clinical features of Stargardt disease include relatively mild rod defects such as delayed dark adaptation, coupled with severe cone defects reflected in macular atrophy and central vision loss. In spite of this clinical divergence, there has been no biochemical study of the effects of ABCA4 deficiency on cones vs. rods. Here we utilize the cone-dominant Abca4−/−/Nrl−/− double knockout mouse to study this issue. We show that as early as post-natal day (P) 30, Abca4−/−/Nrl−/− retinas have significantly fewer rosettes than Abca4+/+/Nrl−/− retinas, a phenotype often associated with accelerated degeneration. Abca4-deficient mice in both the wild-type and cone-dominant background accumulate more of the toxic bisretinoid A2E than their ABCA4-competent counterparts, but Abca4−/−/Nrl−/− eyes generate significantly more A2E per mole of 11-cis-retinal (11-cisRAL) than Abca4−/− eyes. At P120, Abca4−/−/Nrl−/− produced 340±121 pmoles A2E/nmol 11-cisRAL while Abca4−/− produced 50.4±8.05 pmoles A2E/nmol 11-cisRAL. Nevertheless, the retinal pigment epithelium (RPE) of Abca4−/−/Nrl−/− eyes exhibits fewer lipofuscin granules than the RPE of Abca4−/− eyes; at P120: Abca4−/−/Nrl−/− exhibit 0.045±0.013 lipofuscin granules/μm2 of RPE vs. Abca4−/− 0.17±0.030 lipofuscin granules/μm2 of RPE. These data indicate that ABCA4-deficient cones simultaneously generate more A2E than rods and are less able to effectively clear it, and suggest that primary cone toxicity may contribute to Stargardt’s-associated macular vision loss in addition to cone death secondary to RPE atrophy.

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“…1, 2 Photoreceptor injury or degeneration activates a subset of Muller glia cells to express Lif , which controls a cascade of neuroprotective signaling between photoreceptors and Muller cells. 1, 8 These signaling events include activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, 9, 10, 11 and result in the upregulation of several genes important for neuroprotection, including signal transducer and activator of transcription-3 ( Stat3 ), endothelin-2 ( End2 ) and fibroblast growth factor-2 ( Fgf2 ), and for gliosis (glial fibrillary acidic protein, Gfap ). 1, 12 In the absence of LIF, none of these factors is induced, and photoreceptor cell death is accelerated.…”

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confidence: 99%

p38 MAPK signaling acts upstream of LIF-dependent neuroprotection during photoreceptor degeneration

et al. 2013

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In many blinding diseases of the retina, loss of function and thus severe visual impairment results from apoptotic cell death of damaged photoreceptors. In an attempt to survive, injured photoreceptors generate survival signals to induce intercellular protective mechanisms that eventually may rescue photoreceptors from entering an apoptotic death pathway. One such endogenous survival pathway is controlled by leukemia inhibitory factor (LIF), which is produced by a subset of Muller glia cells in response to photoreceptor injury. In the absence of LIF, survival components are not activated and photoreceptor degeneration is accelerated. Although LIF is a crucial factor for photoreceptor survival, the detailed mechanism of its induction in the retina has not been elucidated. Here, we show that administration of tumor necrosis factor-alpha (TNF) was sufficient to fully upregulate Lif expression in Muller cells in vitro and the retina in vivo. Increased Lif expression depended on p38 mitogen-activated protein kinase (MAPK) since inhibition of its activity abolished Lif expression in vitro and in vivo. Inhibition of p38 MAPK activity reduced the Lif expression also in the model of light-induced retinal degeneration and resulted in increased cell death in the light-exposed retina. Thus, expression of Lif in the injured retina and activation of the endogenous survival pathway involve signaling through p38 MAPK.

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Induction of STAT3-related genes in fast degenerating cone photoreceptors of cpfl1 mice

Cited by 26 publications

References 44 publications

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Increased cone sensitivity to ABCA4 deficiency provides insight into macular vision loss in Stargardt's dystrophy

p38 MAPK signaling acts upstream of LIF-dependent neuroprotection during photoreceptor degeneration

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