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Cited by 143Retinal Development and DisordersNeurogenesis and neuroplasticity mechanismsRetinal Diseases and Treatments

Retinal injury, growth factors, and cytokines converge on β-catenin and pStat3 signaling to stimulate retina regeneration

Open access
Wan, Jin, Zhao, Xiao-Feng, Vojtek, Anne, Goldman, Daniel·2014·Cell Reports
DOI 10.1016/j.celrep.2014.08.048PMC PMC4194164
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Abstract

Müller glia (MG) in the zebrafish retina respond to retinal injury by generating multipotent progenitors for retinal repair. Here, we show that Insulin, Igf-1, and fibroblast growth factor (FGF) signaling components are necessary for retina regeneration. Interestingly, these factors synergize with each other and with heparin-binding EGF-like growth factor (HB-EGF) and cytokines to stimulate MG to generate multipotent progenitors in the uninjured retina. These factors act by stimulating a core set of signaling cascades (Mapk/Erk, phosphatidylinositol 3-kinase [PI3K], β-catenin, and pStat3) that are also shared with retinal injury and exhibit a remarkable amount of crosstalk. Our studies suggest that MG both produce and respond to factors that stimulate MG reprogramming and proliferation following retinal injury. The identification of a core set of regeneration-associated signaling pathways required for MG reprogramming not only furthers our understanding of retina regeneration in fish but also suggests targets for enhancing regeneration in mammals.

Integrity signals

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Crossref · 10.1016/j.celrep.2014.08.048

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 59 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Müller glia-derived progenitors in IGF-1/FGF2-treated retinas are multipotent.

    “Using a BrdU lineage tracing strategy, we found that the MG-derived progenitors in IGF-1/FGF2-treated retinas were multipotent (Figures S2E–S2G).”
    Quote in the paperSubstantial claim
  • Findingown data

    Conditional expression of dnFgfr1 suppresses Müller glia proliferation in the injured retina.

    “We found that conditional expression of dnFgfr1 suppressed MG proliferation in the injured retina (Figures 2G and 2H), which is consistent with that found when photoreceptors are damaged (Hochmann et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hochmann et al., 2012 source

      Not checked in the free run.

  • Findingown data

    Low concentrations of Insulin and HB-EGF combined synergistically stimulate Müller glia proliferation in the uninjured retina.

    “Interestingly, when low concentrations of Insulin and HB-EGF were combined, they revealed a remarkable synergy in their ability to stimulate MG proliferation (Figures 1K, 1L, S1J and S1K).”
    Quote in the paperSubstantial claim
  • Findingown data

    Intravitreal injection of human FGF2 has little effect on Müller glia proliferation in the uninjured retina.

    “Like IGF-1, intravitreal injection of FGF2 had little effect on MG proliferation in the uninjured retina (Figure 2I, middle panel).”
    Quote in the paperSubstantial claim
  • Findingown data

    Insulin, Igf-1 and FGF signaling components are necessary for retina regeneration.

    “Here we show that Insulin, Igf-1 and FGF signaling components are necessary for retina regeneration.”
    • Also stated in: § Introduction · plain
      “Here we report that Insulin, IGF-1 and FGF signaling components are necessary for regeneration in the injured zebrafish retina.”
    Quote in the paperSubstantial claim
  • May combine two claims. 38
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Findingown data

    FGF2/IGF-1 treatment does not stimulate cell death or microglia proliferation.

    “FGF2/IGF-1 did not stimulate cell death (Figure S2C) or microglia proliferation (Figure S2D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    These factors act by stimulating a core set of signaling cascades-Mapk/Erk, PI3K, β-catenin and pStat3-that are also shared with retinal injury and show crosstalk.

    “These factors act by stimulating a core set of signaling cascades (Mapk/Erk, PI3K, β-catenin and pStat3) that are also shared with retinal injury and exhibit a remarkable amount of crosstalk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Insulin signaling stimulates Müller glia reprogramming and proliferation in both the injured and uninjured zebrafish retina.

    “Insulin signaling stimulates MG reprogramming and proliferation in the injured and uninjured zebrafish retina”
    • Also stated in: § Insulin signaling stimulates MG reprogramming and proliferation in the injured and uninjured zebrafish retina · hedged
      “Together, the above studies indicate that Insulin signaling participates in injury-induced retina regeneration and that treating an uninjured retina with Insulin is sufficient to stimulate MG reprogramming and the formation of multipotent progenitors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    igfra mRNA increases at 4 dpi and igfbp3 mRNA increases at 6 hpi in both Müller glia and neurons.

    “igfra mRNA increased at 4 dpi and igfbp3 mRNA increased at 6 hpi in both MG and neurons (Figure 2D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Knockdown of Igfbp3 or Igfra suppresses progenitor formation, while knockdown of Igf1rb has no effect.

    “Importantly, MO-mediated knockdown of Igfbp3 or Igfra suppressed progenitor formation, while knockdown of Igf1rb had no effect (Figures 2E and 2F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In growth factor-treated retina, pErk accumulates in quiescent Müller glia and pAkt in photoreceptor outer segments.

    “Similar to that observed in the injured retina (Figure 3D), we found pErk accumulation in quiescent MG and pAkt in photoreceptor outer segments of the growth factor-treated retina (Figures S3D and S3E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The PI3K/Akt inhibitors Ly294002 and PI-103 have no significant effect on cell death, Müller glia morphology, or glutamine synthetase expression.

    “These inhibitors had no significant effect on cell death (Figures 3C and S2I), MG morphology or expression of the MG marker, glutamine synthetase (GS) (Figure S2J).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neither Insulin nor HB-EGF stimulates microglia proliferation even at high concentrations, suggesting their effect is specific to Müller glia.

    “Even at high concentrations that stimulate robust MG proliferation, neither Insulin nor HB-EGF stimulates microglia proliferation (Figures S1C and S1L); suggesting their effect is specific to MG.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    pErk and pAkt increase in Müller glia and photoreceptor outer segments, respectively, throughout the retina within 1 hpi.

    “Interestingly, pErk and pAkt increased in MG and photoreceptor outer segments, respectively, throughout the retina within 1 hpi (Figure S3 A and S3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HB-EGF and Insulin together, or IGF-1 and FGF2 together, dramatically stimulate β-catenin and pStat3 expression in the uninjured retina.

    “However, like their synergistic effect on MG proliferation (Figures 1K, 1L, 2I and 2J), HB-EGF and Insulin or IGF-1 and FGF2 together, dramatically stimulated β-catenin and pStat3 expression (Figures 4D and 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    These factors are specifically induced in Müller glia undergoing reprogramming for retinal repair and are not detected in quiescent Müller glia.

    “Interestingly, all these factors are specifically induced in MG that are reprogramming for retinal repair; they are not detected in quiescent MG.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The growth factors and cytokines tested here did not induce wnt4a mRNA, although retinal injury has been reported to induce it.

    “We note that although wnt4a mRNA has been reported to be induced by retinal injury (Ramachandran et al., 2011), we could not detect its induction by the growth factors or cytokines tested here (data not shown).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ramachandran et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    FGF2 or IGF-1, which are ineffective in stimulating Müller glia proliferation in the uninjured retina, are also ineffective in stimulating β-catenin and pStat3 expression.

    “FGF2 or IGF-1, that were ineffective in stimulating MG proliferation in the uninjured retina (Figures 2I and 2J) were also ineffective in stimulating β-catenin and pStat3 expression (Figure 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only β-catenin and pStat3 were detected in Müller glia-derived progenitors, whereas pErk and pAkt appear restricted to other cell types.

    “However, only β-catenin and pStat3 were detected in MG-derived progenitors, while pErk and pAkt appear to be restricted to other cell types.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Insulin signaling participates in injury-induced retina regeneration, and treating an uninjured retina with Insulin is sufficient to stimulate Müller glia reprogramming and formation of multipotent progenitors.

    “Together, the above studies indicate that Insulin signaling participates in injury-induced retina regeneration and that treating an uninjured retina with Insulin is sufficient to stimulate MG reprogramming and the formation of multipotent progenitors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mapk/Erk has a regulatory role in controlling Müller glia reprogramming after retinal injury or HB-EGF treatment of the uninjured retina.

    “Previous studies identified a regulatory role for Mapk/Erk in controlling MG reprogramming in response to retinal injury or HB-EGF-treatment of the uninjured retina (Wan, 2012)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wan, 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Igf-1 is structurally homologous to Insulin and can bind the Insulin receptor, but its highest affinity is for the Igf-1 receptor.

    “Igf-1 (Insulin-like growth factor 1) is structurally homologous to Insulin and although it can bind the Insulin receptor, its affinity is highest for the Igf-1 receptor (Igf1r) (Wood et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wood et al., 2005 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Müller glia in the postnatal chick retina can be induced to proliferate by intravitreal injection of insulin/FGF2 or IGF-1/FGF2.

    “We were intrigued by reports that MG in the postnatal chick retina could be induced to proliferate in response to intravitreal injection of insulin/FGF2 or IGF-1/FGF2 (Fischer et al., 2002; Fischer and Reh, 2002; Ritchey et al., 2012).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Fischer et al., 2002

      Not checked in the free run.

    • cites Fischer and Reh, 2002

      Not checked in the free run.

    • cites Ritchey et al., 2012 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Wnt/Gsk3β/β-catenin signaling has been implicated in regulating injury-dependent Müller glia proliferation.

    “Wnt/Gsk3β/β-catenin has been implicated in regulating injury-dependent MG proliferation (Meyers et al., 2012; Ramachandran et al., 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Meyers et al., 2012 source

      Not checked in the free run.

    • cites Ramachandran et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After needle poke injury, Müller glia at the injury site proliferate and generate multipotent progenitors for retinal repair.

    “We previously demonstrated that following a needle poke injury, MG at the injury site proliferate and generate multipotent progenitors for retinal repair (Fausett and Goldman, 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fausett and Goldman, 2006 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Igf signaling components are regulated after retinal injury, and Igf signaling regulates formation of Müller glia-derived progenitors in the injured retina.

    “These data indicate that Igf signaling components are regulated following retinal injury and that Igf signaling regulates the formation of MG-derived progenitors in the injured retina.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hbegfa regulates progenitor formation in the injured zebrafish retina, and recombinant HB-EGF stimulates Müller glia to generate progenitors in the uninjured retina.

    “We previously reported that Hbegfa regulates progenitor formation in the injured zebrafish retina and that recombinant HB-EGF stimulates MG to generate progenitors in the uninjured retina (Wan, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wan, 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Zebrafish have two igf1r genes, igf1ra and igf1rb, that often play overlapping roles.

    “Zebrafish harbor 2 igf1r genes, igf1ra and igf1rb that often play overlapping roles (Schlueter et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schlueter et al., 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Igf binding proteins stabilize bound Igfs and modulate their activity.

    “Furthermore, Igf binding proteins stabilize bound Igfs and modulate their activity (Wood et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wood et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Retinal injury stimulates Müller glia to release a variety of growth factors that alone may be ineffective but together synergize to stimulate Müller glia reprogramming and production of multipotent progenitors.

    “Taken together, our data suggest that retinal injury stimulates MG to release of a variety of growth factors that alone may be ineffective, but together synergize to stimulate MG reprogramming and the production of multipotent progenitors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Igfbp3 is the most highly expressed Igfbp and binds most abundantly to Igf-1.

    “Igf binding protein 3 (Igfbp3) is the most highly expressed Igfbp and binds most abundantly to Igf-1(Wood et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wood et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Signaling pathways downstream of the Fgf receptor are sufficiently activated in HB-EGF- and Insulin-treated retinas but not in IGF-1-treated retinas, which explains why IGF-1 needs FGF2 to stimulate Müller glia proliferation.

    “This result suggests that regeneration-associated signaling pathways acting downstream of the Fgf receptor are sufficiently stimulated in HB-EGF and Insulin-treated retinas, but not in IGF-1-treated retinas and hence explains why IGF-1 requires FGF2 to stimulate MG proliferation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Experimenters were blind to the injected material until after data analysis.

    “Experimenters remained blind to the material injected into the vitreous until after data analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Insulin, IGF-1, and FGF-2 stimulate Müller glia proliferation in the postnatal chick retina.

    “Interestingly, Insulin, IGF-1 and FGF-2 stimulate MG proliferation in the postnatal chick retina (Fischer et al., 2002; Ritchey et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Fischer et al., 2002

      Not checked in the free run.

    • cites Ritchey et al., 2012 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Leptin and IL-11 cytokines are both required and enough to drive Müller glia reprogramming and progenitor production in injured and uninjured retina, as reported in the companion paper by Zhao et al.

    “In the accompanying manuscript by Zhao et al., we report that cytokines, like Leptin and IL-11, are necessary and sufficient to stimulate MG reprogramming and progenitor formation in the injured and uninjured retina.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhao et al.

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Injury-responsive Müller glia secrete a variety of factors that drive their own reprogramming and proliferation, and extensive crosstalk among these factors allows signal amplification and localization.

    “We found that injury-responsive MG secrete a variety of factors that drive their own reprogramming and proliferation which, along with extensive crosstalk among these factors, allows for signal amplification and localization.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    pAkt is found in Xenopus and rodent photoreceptor outer segments and is correlated with cell survival.

    “Interestingly, pErk is localized to proliferating MG in the injured chick retina (Fischer et al., 2009) and pAkt is found in Xenopus and rodent photoreceptor outer segments and correlated with cell survival (Dilly and Rajala, 2008; Ivanovic et al., 2011; Jomary et al., 2006; Li et al., 2008; Rajala et al., 2002).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dilly and Rajala, 2008 source

      Not checked in the free run.

    • cites Ivanovic et al., 2011 source

      Not checked in the free run.

    • cites Jomary et al., 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The intravitreal injection method was validated using HB-EGF to stimulate Müller glia proliferation, and a similar validation series was done for Insulin.

    “In the accompanying paper by Xiao et al., we validated our intravitreal injection method using HB-EGF to stimulate MG proliferation. A similar series of validations was done for Insulin (data not shown).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Xiao et al.

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Injection of growth factors or cytokines into the uninjured retina increases expression of additional growth factors and cytokines, which may contribute to their ability to induce Müller glia proliferation.

    “These data suggest that growth factor or cytokine injection into the uninjured retina stimulates the expression of additional growth factors and cytokines and this may contribute to their effectiveness in inducing MG proliferation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Human IGF-1 acts via zebrafish receptors because the mature peptide shares about 81% identity with zebrafish IGF-1, including key receptor-binding residues, and human and zebrafish IGF-IR share over 80% similarity with conserved ligand-binding residues.

    “We suspected human IGF-1 would act via zebrafish receptors because the mature peptide shares ~81% identity with that of zebrafish (Zou et al., 2009), including key residues important for receptor binding (Gauguin et al., 2008). Furthermore, human and zebrafish IGF-IR share over 80% similarity and key residues involved in ligand binding are preserved (Ayaso et al., 2002; Renteria et al., 2008).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Zou et al., 2009 source

      Not checked in the free run.

    • cites Gauguin et al., 2008 source

      Not checked in the free run.

    • cites Ayaso et al., 2002 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    All experiments were performed at least in triplicate and repeated at least twice.

    “All experiments were performed at least in triplicate and repeated at least twice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    After injury activates Müller glia to express growth factor and cytokine-like genes, the resulting gene products act in an autocrine/paracrine manner to drive Müller glia reprogramming and proliferation.

    “Our data suggest that once MG are activated in response to injury by expressing growth factor and cytokine-like genes, these gene products then act in an autocrine/paracrine manner to drive MG reprogramming and proliferation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In mammals, β-catenin is associated with a very limited amount of Müller glia proliferation, while pStat3 is associated with injury-induced gliosis.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Osakada et al., 2007 source

      Not checked in the free run.

    • cites Peterson et al., 2000 source

      Not checked in the free run.

    • cites Rhee et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Activation of Mapk and PI3K signaling is necessary but not sufficient to drive Müller glia proliferation.

    “Together, these data suggest that activation of Mapk and PI3K signaling is necessary, but not sufficient to drive MG proliferation (see FGF2 and IGF-1 panels in Figures S3D and S3E).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All studies were repeated at least three times.

    “All studies were repeated at least 3 times.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The green immunofluorescence seen in the outer nuclear layer is non-specific, because it disappears when a red-fluorophore-coupled secondary antibody is used.

    “The green immunofluorescence detected in the ONL appears to be non-specific since it is not detected when we used a secondary antibody coupled to a red Fluor (Figure S5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    These factors act in an autocrine or paracrine manner to promote Müller glia reprogramming and proliferation.

    “Together, our data suggests that 1) retinal injury results in the release of a variety of growth factors and cytokines by MG at the injury site; 2) these factors synergize with each other and act in an autocrine/paracrine manner to stimulate MG reprogramming and proliferation; and 3) this proliferation is mediated by activation of β-catenin and pStat3 signaling pathways”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Human Insulin is active in zebrafish because its mature form shares extensive amino acid identity with zebrafish Insulin and was previously shown to activate zebrafish Insulin receptors.

    “We suspected that human Insulin would be active in zebrafish because its mature form exhibits extensive amino acid identity (~77%) with that of zebrafish and it was previously shown to activate zebrafish Insulin receptors (Papasani et al., 2006; Toyoshima et al., 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Papasani et al., 2006 source

      Not checked in the free run.

    • cites Toyoshima et al., 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    pErk is localized to proliferating Müller glia in the injured chick retina.

    “Interestingly, pErk is localized to proliferating MG in the injured chick retina (Fischer et al., 2009) and pAkt is found in Xenopus and rodent photoreceptor outer segments and correlated with cell survival (Dilly and Rajala, 2008; Ivanovic et al., 2011; Jomary et al., 2006; Li et al., 2008; Rajala et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fischer et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    There is extensive crosstalk among growth factors, cytokines, and their signaling cascades, and this crosstalk contributes to their effectiveness in stimulating Müller glia proliferation.

    “Together, these studies indicate a remarkable amount of crosstalk between growth factors, cytokines and their signaling cascades and suggest that this crosstalk contributes to the effectiveness of these factors ability to stimulate MG proliferation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    A positive control with ouabain was included in the TUNEL assay.

    “Eyes intravitreally injected of 3µM ouabain were included as a positive control (Fimbel et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fimbel et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Similar results were obtained regardless of the method used for intravitreal injection.

    “Similar results were obtained regardless of the method used for intravitreal injection.”
    Quote in the paperNot a substantial claim
47 of 47

  • The paper relies on this without support.

    Mammals cannot regenerate a damaged retina.

    “Unfortunately mammals are unable to regenerate a damaged retina.”

  • The paper relies on this without support.

    The mechanisms that drive Müller glia reprogramming are poorly understood.

    “The mechanisms driving MG reprogramming are poorly understood.”

  • The paper relies on this without support.

    Müller glia proliferation is critical for successful retina regeneration.

    “MG proliferation is critical for successful retina regeneration.”

  • The paper relies on this without support.

    It is unknown whether additional signaling systems contribute to Müller glia reprogramming and retina regeneration, or whether the signaling cascades reflect the type of stimulus used to induce a Müller glia response.

    “Whether additional signaling systems contribute to MG reprogramming and retina regeneration are not known, nor is it known if these signaling cascades reflect the type of stimulus used to induce a MG response.”

  • The authors state this as an assumption.

    The injury signals that trigger Müller glia reprogramming, where they come from, and how they work are poorly understood.

    “The nature of the injury signals, their derivation and their mechanism of action are poorly understood.”

  • The authors state this as an assumption.

    The endogenous factors that mediate injury-dependent Müller glia reprogramming and proliferation are poorly characterized.

    “Although zebrafish have been known for some time to have the capacity to regenerate a damaged retina, the endogenous factors mediating injury-dependent MG reprogramming and proliferation remain poorly characterized.”

  • The paper relies on this without support.

    Zebrafish Müller glia can respond to retinal injury by reprogramming to acquire retinal stem cell properties, proliferate, and regenerate all retinal cell types.

    “Zebrafish MG are able to respond to retinal injury by reprogramming their genome so they acquire retinal stem cell characteristics that allow them to proliferate and regenerate all retinal cell types.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In zebrafish, retina regeneration after injury depends on Müller glia dedifferentiation into a cycling population of multipotent progenitors via an EGFR/MAPK signal transduction cascade that regulates the expression of regeneration-associated genes such as PAX6.

    “In zebrafish, retina regeneration after injury depends on Müller glia (MG) dedifferentiation into a cycling population of multipotent progenitors via an EGFR/MAPK signal transduction cascade that regulates the expression of regeneration-associated genes such as PAX6 [ 18 , 19 ].”

    From MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges (2023) · cites this paper as [18]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

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Authors
Wan, J., Zhao, X.-F., Vojtek, A., & Goldman, D.
Affiliations
University of Michigan (US)
Corresponding author
Goldman, Daniel
ORCID
Goldman, Daniel
Venue
Cell Reports
Publisher
Elsevier BV
Published
2014-10
Volume
9
Issue
1
Pages
285-297
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2014.08.048
PMC
PMC4194164
OpenAlex
W2075732658
Semantic Scholar
b322759f7387260f2909e9476d27fc17e6cf42e5
Cited by
143
References
52
Citations by year
2026: 5 · 2025: 8 · 2024: 15 · 2023: 14 · 2022: 16 · 2021: 18 · 2020: 11 · 2019: 11 · 2018: 11 · 2017: 14 · 2016: 9 · 2015: 9 · 2014: 2
FWCI
4.62
Type
journal article
Language
en
Update notices
erratum (2014-10-23)
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Eye Institute (R01EY018132)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Keywords
retinal regeneration, Müller cells, retinal damage, zebrafish, insulin signaling, IGF-1 signaling, FGF signaling, HB-EGF, cytokines, β-catenin signaling, STAT3 signaling, ERK signaling, PI3K signaling, signaling crosstalk, glial reprogramming, multipotent progenitors
MeSH terms
Animals, Cell Differentiation, Nerve Regeneration, Retina, Zebrafish, Signal Transduction, Cytokines, Zebrafish Proteins, Animals, Genetically Modified, Intercellular Signaling Peptides and Proteins, STAT3 Transcription Factor, beta Catenin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-29.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-29.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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