STAT3-Mediated Signaling in the Determination of Rod Photoreceptor Cell Fate in Mouse Retina

Zhang, Samuel Shao Min; Wei, Ji-Ye; Qin, Hua; Zhang, Lixin; Xie, Bing; Hui, Pei; Deisseroth, Albert; Barnstable, Colin J.; Fu, Xin

doi:10.1167/iovs.04-0003

Cited by 58 publications

(64 citation statements)

References 52 publications

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“…In contrast, blocking phospho-STAT activities by either the phosphotyrosyl peptide inhibitor or a dominant-negative STAT3 enhances rod photoreceptor differentiation in vitro. Because these results were obtained in the absence of exogenous cytokines, they strongly support a role for endogenous STAT3 activation in negative regulation of photoreceptor differentiation in the postnatal retina (Zhang et al, 2004). Ozawa et al (2004) showed recently that abolishing STAT3 activity in the embryonic retina results in precocious expression of the homeobox gene Crx, which is required for terminal differentiation of rod and cone photoreceptors (Furukawa et al, 1999).…”

Section: Discussionmentioning

confidence: 65%

Cytokine-Induced Activation of Signal Transducer and Activator of Transcription in Photoreceptor Precursors Regulates Rod Differentiation in the Developing Mouse Retina

Rhee¹,

Goureau²,

Chen³

et al. 2004

J. Neurosci.

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has no effect on rod photoreceptor differentiation in vitro. Furthermore, disrupting the function of epidermal growth factor (EGF) receptors, which modulate rod development in vivo, indicates that the EGF family of ligands does not mediate the inhibitory effect of cytokine on rod differentiation. These results demonstrate that cytokine signal transduction is dynamic and heterogeneous in the developing retina, and that endogenous ligand-induced STAT activation in retinal progenitor and/or photoreceptor precursor cells plays an important role in regulating photoreceptor development.

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Section: Discussionmentioning

confidence: 65%

Cytokine-Induced Activation of Signal Transducer and Activator of Transcription in Photoreceptor Precursors Regulates Rod Differentiation in the Developing Mouse Retina

Rhee¹,

Goureau²,

Chen³

et al. 2004

J. Neurosci.

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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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“…Immunohistochemistry-Methods were as previously described (35). Antigen retrieval was achieved by boiling samples for 5 min in 10 mM citrate buffer, pH 6.0.…”

Section: Methodsmentioning

confidence: 99%

Developmentally Regulated Linker Histone H1c Promotes Heterochromatin Condensation and Mediates Structural Integrity of Rod Photoreceptors in Mouse Retina

Popova

Grigoryev

Fan

et al. 2013

Journal of Biological Chemistry

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Background: Heterochromatin condenses in the middle of rod cell nuclei during retina maturation. Results: The level of linker histone H1c increases during retina maturation. Rod photoreceptors in triple H1 knock-out mice have less compact chromatin. Conclusion: H1c is a key architectural factor for chromatin condensation in the rod photoreceptor. Significance: Histone H1c expression may be genetically modified to promote rod photoreceptor maturation and retina integrity.Mature rod photoreceptor cells contain very small nuclei with tightly condensed heterochromatin. We observed that during mouse rod maturation, the nucleosomal repeat length increases from 190 bp at postnatal day 1 to 206 bp in the adult retina. At the same time, the total level of linker histone H1 increased reaching the ratio of 1.3 molecules of total H1 per nucleosome, mostly via a dramatic increase in H1c. Genetic elimination of the histone H1c gene is functionally compensated by other histone variants. However, retinas in H1c/H1e/H1 0 triple knock-outs have photoreceptors with bigger nuclei, decreased heterochromatin area, and notable morphological changes suggesting that the process of chromatin condensation and rod cell structural integrity are partly impaired. In triple knock-outs, nuclear chromatin exposed several epigenetic histone modification marks masked in the wild type chromatin. Dramatic changes in exposure of a repressive chromatin mark, H3K9me2, indicate that during development linker histone plays a role in establishing the facultative heterochromatin territory and architecture in the nucleus. During retina development, the H1c gene and its promoter acquired epigenetic patterns typical of rod-specific genes. Our data suggest that histone H1c gene expression is developmentally up-regulated to promote facultative heterochromatin in mature rod photoreceptors.During mammalian development, cells committed to differentiate into a specific tissue withdraw from the cell cycle and start a process of tissue maturation that involves up-regulation of genes specific for the differentiated tissue and down-regulation of genes specific for progenitor cells (1, 2). This developmentally regulated process culminates in formation of compact blocks of heterochromatin inside the nuclei and spatial segregation of heterochromatin and euchromatin domains (3). Chromatin condensation prevents certain transcription factors from activating genes in the compact chromatin (4). Recent studies suggest that each tissue type has its own unique program that orchestrates tissue maturation, with specific sets of chromatin architectural and remodeling proteins, histone modifications, and micro-RNA (5-12).The mammalian retina is a part of the CNS and is derived from the optic cup, an outgrowth of forebrain neuroepithelium formed early in CNS development. Six major neuronal and one glial cell types are generated from the multipotential retinal progenitors in a stereotypic temporal sequence. In mice the terminal differentiation of retinal cells spans from embryonic day ...

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STAT3-Mediated Signaling in the Determination of Rod Photoreceptor Cell Fate in Mouse Retina

Abstract: These results indicate that STAT3, but not MAPK, can critically regulate photoreceptor development during mouse retina development.

Cited by 58 publications

References 52 publications

Cytokine-Induced Activation of Signal Transducer and Activator of Transcription in Photoreceptor Precursors Regulates Rod Differentiation in the Developing Mouse Retina

Cytokine-Induced Activation of Signal Transducer and Activator of Transcription in Photoreceptor Precursors Regulates Rod Differentiation in the Developing Mouse Retina

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

Developmentally Regulated Linker Histone H1c Promotes Heterochromatin Condensation and Mediates Structural Integrity of Rod Photoreceptors in Mouse Retina

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