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Ciliary Neurotrophic Factor and Stress Stimuli Activate the Jak-STAT Pathway in Retinal Neurons and Glia
Open accessAbstract
Ciliary neurotrophic factor (CNTF) is pleiotrophic for central, peripheral, and sensory neurons. In the mature retina, CNTF treatment enhances survival of retinal ganglion and photoreceptor cells exposed to otherwise lethal perturbation. To understand its mechanism of action in vivo,the adult rat retina was used as a model to investigate CNTF-mediated activation of Janus kinase/signal transducer and activator of transcription (Jak-STAT) and ras-mitogen activated protein kinase (ras-MAPK). Intravitreal injection of Axokine, an analog of CNTF, phosphorylates STAT3 and MAPK and produces delayed upregulation of total STAT3 and STAT1 protein in rat retina. Activated STAT3 is predominantly localized in nuclei of retinal Müller (glial) cells, ganglion cells, and astrocytes, but not in photoreceptors. Although CNTF α-receptor (CNTFRα) mRNA and protein are localized predominantly if not exclusively in retinal neurons, coincident CNTF-mediated STAT3 signaling was observed in both glia and neurons. CNTF-induced activation of Jak-STAT signaling prompted us to investigate STAT3 phosphorylation after a variety of stress-mediated, conditioning stimuli. We show that STAT3 is activated in the retina after exposure to subtoxic bright light, mechanical trauma, and systemic administration of the α 2-adrenergic agonist xylazine, all of which have been shown previously to condition photoreceptors to resist light-induced degeneration. These results demonstrate that CNTF directly stimulates Jak-STAT and ras-MAPK cascades in vivo and strongly suggest that STAT3 signaling is an underlying component of neural responsiveness to stress stimuli. The observation that CNTF activates STAT3 in ganglion cells, but not in photoreceptors, suggests that Jak-STAT signaling influences neuronal survival via both direct and indirect modes of action.
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“It is interesting that in mammals, β-catenin has been associated with a very limited amount of MG proliferation while pStat3 has been associated with injury-induced gliosis (Osakada et al., 2007; Peterson et al., 2000; Rhee et al., 2013; Xue et al., 2011).”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Peterson et al., 2000
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Metadata
- Authors
- Peterson, W. M., Wang, Q., Tzekova, R., & Wiegand, S. J.
- Affiliations
- Regeneron (United States) (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2000-06-01
- Volume
- 20
- Issue
- 11
- Pages
- 4081-4090
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6772642
- OpenAlex
- W1493793044
- Cited by
- 267
- References
- 59
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 9 · 2019: 2 · 2018: 4 · 2017: 6 · 2016: 10 · 2015: 13 · 2014: 11 · 2013: 16 · 2012: 13
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- ciliary neurotrophic factor, JAK/STAT signaling, STAT3, STAT1, retinal neurons, retinal glia, retinal ganglion cells, photoreceptors, Müller cells, astrocytes, RAS/MAPK pathway, light-induced retinal degeneration, xylazine, mechanical trauma, neuroprotection
- MeSH terms
- Animals, Conditioning, Psychological, DNA-Binding Proteins, Glial Fibrillary Acidic Protein, Humans, Immunohistochemistry, Male, Nerve Tissue Proteins, Neuroglia, Neurons, Phosphorylation, Photic Stimulation, Retina, Stress, Psychological, Transcription, Genetic, Signal Transduction, Trans-Activators, Rats, Sprague-Dawley, MAP Kinase Kinase Kinases, Ciliary Neurotrophic Factor, Extracellular Signal-Regulated MAP Kinases, STAT3 Transcription Factor, Rats
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