CNTF induces photoreceptor neuroprotection and Müller glial cell proliferation through two different signaling pathways in the adult zebrafish retina
Abstract
Ciliary neurotrophic factor (CNTF) acts in several processes in the vertebrate retina, including neuroprotection of photoreceptors in the stressed adult retina and regulation of neuronal progenitor cell proliferation during retinal development. However, the signaling pathway it utilizes (Jak/Stat, MAPK, or Akt) in these processes is ambiguous. Because dark-adapted albino zebrafish exhibit light-induced rod and cone cell death and subsequently regenerate the lost photoreceptor cells, zebrafish should be a useful model to study the role of CNTF in both neuroprotection and neuronal progenitor cell proliferation. We therefore investigated the potential roles of CNTF in both the undamaged and light-damaged adult zebrafish retinas. Intraocular injection of CNTF suppressed light-induced photoreceptor cell death, which then failed to exhibit the regeneration response that is marked by proliferating Müller glia and neuronal progenitor cells. Inhibiting the MAPK signaling pathway, but neither the Stat3 nor Akt pathways, significantly reduced the CNTF-mediated neuroprotection of light-induced photoreceptor cell death. Intraocular injection of CNTF into non-light-treated (undamaged) eyes mimicked constant intense light treatment by increasing Stat3 expression in Müller glia followed by increasing the number of proliferating Müller glia and neuronal progenitors. Knockdown of Stat3 expression in the CNTF-injected non-light-treated retinas significantly reduced the number of proliferating Müller glia, while coinjection of CNTF with either MAPK or Akt inhibitors did not inhibit the CNTF-induced Müller glia proliferation. Thus, CNTF utilizes a MAPK-dependant signaling pathway in neuroprotection of light-induced photoreceptor cell death and a Stat3-dependant signaling pathway to stimulate Müller glia proliferation.
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CNTF can drive Müller glia proliferation in uninjured retinas, but in damaged retinas it appears neuroprotective and inhibits proliferation.
“CNTF can stimulate MG proliferation in the uninjured retina, but seems to be neuroprotective in the damaged retina where it inhibits MG proliferation”
From HB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration (2012) · cites this paper as Kassen et al., 2009
Previous studies indicate that Mapk/Erk, Gsk3β/β-catenin and Jak/Stat3 signaling regulate Müller glia-dependent progenitor formation in the injured retina.
“Previous studies (Kassen et al., 2009; Meyers et al., 2012; Nelson et al., 2012; Ramachandran et al., 2011; Wan, 2012), along with the accompanying paper by Zhao et al., indicate that Mapk/Erk, Gsk3 β/β-catenin and Jak/Stat3 signaling regulate MG-dependent progenitor formation in the injured retina.”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Kassen et al., 2009
Without retinal injury, Müller glia can be forced to reprogram by growth factors such as HB-EGF and by cytokines.
“Furthermore, in the absence of retinal injury MG can be forced to reprogram by growth factors, like HB-EGF (Wan, 2012) and cytokines (see accompanying manuscript by Zhao et al.) (Kassen et al., 2009).”
From Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration (2014) · cites this paper as Kassen et al., 2009
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HB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration
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“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript include FGF2 and insulin that in combination stimulate MG proliferation in the postnatal chick retina (Fischer et al., 2002) and CNTF that stimulates MG proliferation in zebrafish (Kassen et al., 2009).”
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“Previous studies (Kassen et al., 2009; Meyers et al., 2012; Nelson et al., 2012; Ramachandran et al., 2011; Wan, 2012), along with the accompanying paper by Zhao et al.”
BackgroundResultNelson, C. M., Gorsuch, R. A., Bailey, T. J., Ackerman, K. M., Kassen, S. C., & Hyde, D. R. (2012) · Journal of Comparative Neurology · doi:10.1002/cne.23213 · Cited by 123 · see citing works
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Complement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration
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- Authors
- Kassen, S. C., Thummel, R., Campochiaro, L. A., Harding, M. J., Bennett, N. A., & Hyde, D. R.
- Affiliations
- University of Notre Dame (US)
- Corresponding author
- Hyde, David R.
- Venue
- Experimental Eye Research
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 88
- Issue
- 6
- Pages
- 1051-1064
- ISSN
- 0014-4835 (ISSN-L)
- OpenAlex
- W1969182690
- Cited by
- 116
- References
- 62
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 1 · 2023: 7 · 2022: 5 · 2021: 12 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 4 · 2015: 10 · 2014: 7 · 2013: 11 · 2012: 9
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Eye Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- ciliary neurotrophic factor, photoreceptor regeneration, MAPK signaling, STAT3 signaling, Akt signaling, neural progenitor cells, zebrafish retina, retinal development
- MeSH terms
- Animals, Nerve Regeneration, Neuroglia, Photic Stimulation, Radiation Injuries, Retina, Retinal Diseases, Stem Cells, Zebrafish, Signal Transduction, Apoptosis, Neuroprotective Agents, In Situ Nick-End Labeling, Photoreceptor Cells, Vertebrate, Ciliary Neurotrophic Factor, MAP Kinase Signaling System, Cell Proliferation, STAT3 Transcription Factor, Opsins
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