Leukemia Inhibitory Factor Blocks Expression of Crx and Nrl Transcription Factors to Inhibit Photoreceptor Differentiation

Graham, D.R.; Overbeek, Paul A.; Ash, John D.

doi:10.1167/iovs.05-0129

Cited by 34 publications

(38 citation statements)

References 64 publications

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“…Consequently, inhibition of rod differentiation by LIF was sustained in explants grown for a maximum of 12 days. Moreover, overexpression of LIF in the mouse eye results in an almost complete suppression of rod differentiation throughout the period of retinal development (Graham et al 2005). Taken together, these results support the hypothesis that rod development in vivo is transiently inhibited by a CNTFRα-mediated signal, the action of which is then terminated by the downregulation of the receptor to permit terminal differentiation.…”

Section: Responsiveness Of Developing Photoreceptors To Gp130-associasupporting

confidence: 71%

“…However, this does not exclude the existence of such a mechanism in vivo that might crucially depend on the effective concentrations of the factors. The overexpression of LIF in the eyes of transgenic mice has recently shown that cytokine signaling during postnatal retinal development inhibits not only the expression of phototransduction components, representing markers for terminally differentiated photoreceptors, but also that of key transcription factors, such as crx, nrl and Nr2e3, which are required for the phenotypic maturation of the progenitor cells (Graham et al 2005). These results indicate that the action of CNTF-like cytokines arrests developing photoreceptor at a precursor cell state and suggest that the downregulation of CNTFRα is a precondition for the initiation of terminal photoreceptor differentiation.…”

Section: Regulation Of Cntf Receptor Expressionmentioning

confidence: 99%

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Regulation of cytokine signaling components in developing rat retina correlates with transient inhibition of rod differentiation by CNTF

et al. 2008

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Ciliary neurotrophic factor (CNTF) is known to inhibit the differentiation of rod photoreceptors from postmitotic precursor cells. During early postnatal development, photoreceptor precursors lose their responsiveness to CNTF. The underlying events causing this change in responsiveness are unknown. Moreover, whether rods express CNTF receptor alpha, a prerequisite for a direct response to the factor, is controversial. Since morphological studies have previously produced conflicting results, we have analyzed the expression of cytokine receptor components and potential ligands in the rat photoreceptor layer by real-time reverse transcription with the polymerase chain reaction after laser microdissection and by immunoblotting. Cytokine effects on rods were studied in explant cultures from newborn rat retina. CNTF receptor alpha (CNTFR alpha) and leukemia inhibitory factor receptor ss (LIFRss) were expressed in immature photoreceptors. Expression of the CNTF-specific alpha-subunit (but not of LIFRss) was downregulated specifically in the photoreceptor layer in parallel with the appearance of opsin-positive rods. The decrease of CNTFR alpha levels in explant cultures was closely correlated with the loss of precursor cell responsiveness to CNTF. Increasing the CNTF concentration in the culture medium led to prolonged CNTFR alpha expression and, concomitantly, to persistent inhibition of rod differentiation. Application of CNTF and LIF in vitro induced phosphorylation of STAT3. Inducibility of STAT3 activation by CNTF decreased with photoreceptor maturation, whereas the LIF effect persisted. Our results thus indicate that CNTF acts directly on photoreceptor precursors inhibiting their differentiation via activation of the JAK/STAT3 signal transduction pathway, and that this effect is temporally limited because of the downregulation of CNTFR alpha.

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Section: Responsiveness Of Developing Photoreceptors To Gp130-associasupporting

confidence: 71%

Section: Regulation Of Cntf Receptor Expressionmentioning

confidence: 99%

Regulation of cytokine signaling components in developing rat retina correlates with transient inhibition of rod differentiation by CNTF

et al. 2008

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“…We generated populations in which all the cell aggregates contained Crx-positive cells ( 65% of Following the scale up of the ESC differentiation protocol to isolate populations for transplantation, we found very few Nrl expressing cells. This may be due to several reasons including increased concentrations of inhibitory factors derived from other retinal cell types, such as ciliary neurotrophic factor produced by astrocytes and glial cells [26][27][28][29], and previously shown to inhibit rod differentiation [30,31] and to block Nrl and Crx expression [32]. In vivo retinal development involves gradients of secreted signaling molecules, such as fibroblast growth factor (FGF) 2 and Shh [33], that may not be present in the adherent ESC-derived cultures.…”

Section: Discussionmentioning

confidence: 99%

Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors

West¹,

Gonzalez‐Cordero²,

Hippert³

et al. 2012

Stem Cells

119

116

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Retinal degeneration is a leading cause of irreversible blindness in the developed world. Differentiation of retinal cells, including photoreceptors, from both mouse and human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), potentially provide a renewable source of cells for retinal transplantation. Previously, we have shown both the functional integration of transplanted rod photoreceptor precursors, isolated from the postnatal retina, in the adult murine retina, and photoreceptor cell generation by stepwise treatment of ESCs with defined factors. In this study, we assessed the extent to which this protocol recapitulates retinal development and also evaluated differentiation and integration of ESC-derived retinal cells following transplantation using our established procedures. Optimized retinal differentiation via isolation of Rax.GFP retinal progenitors recreated a retinal niche and increased the yield of Crx 1 and Rhodopsin 1 photoreceptors. Rod birth peaked at day 20 of culture and expression of the early photoreceptor markers Crx and Nrl increased until day 28. Nrl levels were low in ESC-derived populations compared with developing retinae. Transplantation of early stage retinal cultures produced large tumors, which were avoided by prolonged retinal differentiation (up to day 28) prior to transplantation. Integrated mature photoreceptors were not observed in the adult retina, even when more than 60% of transplanted ESCderived cells expressed Crx. We conclude that exclusion of proliferative cells from ESC-derived cultures is essential for effective transplantation. Despite showing expression profiles characteristic of immature photoreceptors, the ESC-derived precursors generated using this protocol did not display transplantation competence equivalent to precursors from the postnatal retina. STEM CELLS

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“…However, little is known regarding the mechanism of protection. In addition, several adverse consequences of overstimulation of this receptor have been reported, including gliosis (38), inhibition of neural function (17,19,39,40), and altered developmental states (41)(42)(43). Therefore, specific knowledge of the mechanism for gp130-induced protection is essential for the development of neuroprotective therapies to avoid these side effects.…”

Section: Discussionmentioning

confidence: 99%

Preconditioning-induced protection of photoreceptors requires activation of the signal-transducing receptor gp130 in photoreceptors

Ueki

Chollangi

et al. 2009

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

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Retinal degenerations are a class of neurodegenerative disorders that ultimately lead to blindness due to the death of retinal photoreceptors. In most cases, death is the result of long-term exposure to environmental, inflammatory, and genetic insults. In age-related macular degeneration, significant vision loss may take up to 70 -80 years to develop. The protracted time to develop blindness suggests that retinal neurons have an endogenous mechanism for protection from chronic injury. Previous studies have shown that endogenous protective mechanisms can be induced by preconditioning animals with sublethal bright cyclic light. Such preconditioning can protect photoreceptors from a subsequent damaging insult and is thought to be accomplished through induced expression of protective factors. Some of the factors shown to be associated with protection bind and activate the signal transducing receptor gp130. To determine whether stress-induced endogenous protection of photoreceptors requires gp130, we generated conditional gp130 knockout (KO) mice with the Cre/lox system and used light-preconditioning to induce neuroprotection in these mice. Functional and morphological analyses demonstrated that the retina-specific gp130 KO impaired preconditioning-induced endogenous protection. Photoreceptor-specific gp130 KO mice had reduced protection, although the Mü ller cell KO mice did not, thus gp130-induced protection was restricted to photoreceptors. Using an animal model of retinitis pigmentosa, we found that the photoreceptor-specific gp130 KO increased sensitivity to genetically induced photoreceptor cell death, demonstrating that gp130 activation in photoreceptors had a general protective role independent of whether stress was caused by light or genetic mutations.IL6 signal transducing receptor ͉ neuroprotection ͉ conditional gp130 knockout ͉ inherited retinal degeneration ͉ light damage T he signal-transducing receptor gp130 is a common receptor for the IL-6 family of cytokines, such as ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and cardiotrophin-like cytokine (CLC). Use of these cytokines has been shown to be neuroprotective in both the central and peripheral nervous systems, suggesting that this receptor and its signal transduction pathways may be important for the design of neuroprotective therapeutics (1-4).Up-regulation of protective cytokines by acute or chronic stress has been observed in several studies. Mild light stress has been shown to induce endogenous protection of photoreceptors from a subsequent light damage, and protection coincided with prolonged up-regulation of neurotrophic factors (5). bFGF mRNA expression was up-regulated in mice homozygous for the rd1 mutation in the PDE6b gene (a model of retinitis pigmentosa) (6). Elevated levels of bFGF and/or CNTF expression in the retina were also found in light-induced as well as inherited models of photoreceptor degeneration in both mice and rats (7,8). LIF and CLC were also up-regulated by stress from constant light exposure in ...

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Leukemia Inhibitory Factor Blocks Expression of Crx and Nrl Transcription Factors to Inhibit Photoreceptor Differentiation

Abstract: LIF expression did not appear to alter photoreceptor cell fate specification, but it inhibited subsequent differentiation. These results suggest that gp130 ligands can inhibit photoreceptor functional differentiation by reducing Crx- and Nrl-dependent transcription.

Cited by 34 publications

References 64 publications

Regulation of cytokine signaling components in developing rat retina correlates with transient inhibition of rod differentiation by CNTF

Regulation of cytokine signaling components in developing rat retina correlates with transient inhibition of rod differentiation by CNTF

Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors

Preconditioning-induced protection of photoreceptors requires activation of the signal-transducing receptor gp130 in photoreceptors

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