Differential role of Jak‐STAT signaling in retinal degenerations

Samardzija, Marijana; Wenzel, Andreas; Aufenberg, Svenja; Thiersch, Markus; Remé, Charlotte E.; Grimm, Christian

doi:10.1096/fj.06-5895fje

Cited by 109 publications

(126 citation statements)

References 61 publications

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“…JAKMIP1 interacts with Tyk2, a member of Janus kinase family, which has been shown to control the survival and proliferation of retinal cells (Samardzija et al, 2006). LIFR, together with its ligand, leukemia inhibitory factor (LIF), also participates in neuroprotection by activating an endogenous rescue pathway that protects viable photoreceptor cells (Bürgi, Samardzija, & Grimm, 2009).…”

Section: Resultsmentioning

confidence: 99%

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

et al. 2018

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Aging is a phenomenon that is associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision‐threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. iERM is characterized by fibrous tissue developing on the surface of the macula, which leads to biomechanical and biochemical macular damage. MH is a small breakage in the macula and is associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry‐based label‐free quantitative proteomics analysis of the vitreous proteomes from patients with iERM and MH to identify the key proteins, as well as the multiple interconnected biochemical pathways, contributing to the development of these diseases. We identified a total of 1,014 unique proteins, many of which are linked to inflammation and the complement cascade, revealing the inflammation processes in retinal diseases. Additionally, we detected a profound difference in the proteomes of iEMR and MH compared to those of diabetic retinopathy with macular edema and rhegmatogenous retinal detachment. A large number of neuronal proteins were present at higher levels in the iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins, and signaling molecules, pointing toward the important role of neurodegenerative component in the pathogenesis of age‐related vitreoretinal diseases. Despite them having marked similarities, several unique vitreous proteins were identified in both iERM and MH, from which candidate targets for new diagnostic and therapeutic approaches can be provided.

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Section: Resultsmentioning

confidence: 99%

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

et al. 2018

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“…Exposure to high levels of white light induces photoreceptor degeneration and activates a signaling cascade which includes leukemia inhibitory factor (LIF), Janus kinase 2 (Jak2), signal transducer and activator of transcription 1 (STAT1) and STAT3 (Samardzija et al, 2006a). A similar retinal response has been observed in models of inherited retinal degeneration (Samardzija et al, 2006a).…”

Section: Introductionmentioning

confidence: 86%

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

Joly¹,

Lange²,

Thiersch³

et al. 2008

J. Neurosci.

120

168

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Survival and death of photoreceptors in degenerative diseases of the retina is controlled by a multitude of genes and endogenous factors. Some genes may be involved in the degenerative process itself whereas others may be part of an endogenous defense system. We show in two models of retinal degeneration that photoreceptor death strongly induces expression of leukemia inhibitory factor (LIF) in a subset of Muller glia cells in the inner nuclear layer of the retina. LIF expression is essential to induce an extensive intraretinal signaling system which includes Muller cells and photoreceptors and is characterized by an upregulation of Edn2, STAT3, FGF2 and GFAP. In the absence of LIF, Muller cells remain quiescent, the signaling system is not activated and retinal degeneration is strongly accelerated. Intravitreal application of recombinant LIF induces the full molecular pathway including the activation of Muller cells in wild-type and Lif -/-mice. Interruption of the signaling cascade by an Edn2 receptor antagonist increases whereas activation of the receptor decreases photoreceptor cell death. Thus, LIF is essential and sufficient to activate an extensive molecular defense response to photoreceptor injury. Our data establish LIF as a Muller cell derived neuronal survival factor which controls an intrinsic protective mechanism that includes Edn2 signaling to support photoreceptor cell survival and to preserve vision in the injured retina.

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“…Growth factor-induced activation of Akt has been shown in transformed retinal neurons (Barber et al, 2001) and mouse models of retinal degeneration (Samardzija et al, 2006). In situ hybridizations have shown that all three Akt mRNAs are present in different layers of the retina (Reiter et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Nonredundant Role of Akt2 for Neuroprotection of Rod Photoreceptor Cells from Light-Induced Cell Death

et al. 2007

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The Akt kinases mediate cell survival through phosphorylation and inactivation of apoptotic machinery components. Akt signaling provides a trophic signal for transformed retinal neurons in culture, but the in vivo role of Akt activity is unknown. In this study, we found that all three Akt isoforms were expressed in rod photoreceptor cells. We investigated the functional roles of Akt1 and Akt2, two of the isoforms of Akt, and their biological significance in light-induced retinal degeneration. Consistent with the hypothesis that Akt activity is important to circumvent stress-induced apoptosis, herein we report the novel finding that rod photoreceptor cells in Akt2 knock-out mice exhibited a significantly greater sensitivity to stress-induced cell death than rods in heterozygous or wild-type mice. Under similar conditions, Akt1 deletion had no effect on the retina. The presence of three Akt isoforms in the retina is suggestive of a functional redundancy; however, our studies clearly demonstrate that, under stress, Akt1 and Akt3 cannot complement the specific survival signals driven by Akt2. Furthermore, we show that Akt2 is specially activated is response to light stress. The results presented in this study provide the first direct evidence that Akt2 has a nonredundant neuroprotective role in photoreceptor survival and maintenance.

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Differential role of Jak‐STAT signaling in retinal degenerations

Cited by 109 publications

References 61 publications

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

Nonredundant Role of Akt2 for Neuroprotection of Rod Photoreceptor Cells from Light-Induced Cell Death

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