The Experts below are selected from a list of 123408 Experts worldwide ranked by ideXlab platform
Michael Housset - One of the best experts on this subject based on the ideXlab platform.
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loss of otx2 in the adult retina disrupts retinal pigment epithelium function causing photoreceptor degeneration
The Journal of Neuroscience, 2013Co-Authors: Michael Housset, Alexander Samuel, Mohamed Ettaiche, Alexis A Bemelmans, Francis Beby, Nathalie BillonAbstract:Photoreceptors are specialized neurons of the retina that receive nursing from the adjacent retinal pigment epithelium (RPE). Frequent in the elderly, photoreceptor loss can originate from primary dysfunction of either cell type. Despite intense interest in the etiology of these diseases, early molecular actors of late-onset photoreceptor degeneration remain elusive, mostly because of the lack of dedicated models. Conditional Otx2 ablation in the adult mouse retina elicits photoreceptor degeneration, providing a new model of late-onset neuronal disease. Here, we use this model to identify the earliest events after Otx2 ablation. Electroretinography and gene expression analyses suggest a nonautonomous, RPE-dependent origin for photoreceptor degeneration. This is confirmed by RPE-specific ablation of Otx2, which results in similar photoreceptor degeneration. In contrast, constitutive Otx2 expression in RPE cells prevents degeneration of Photoreceptors in Otx2-ablated retinas. We use chromatin immunoprecipitation followed by massive sequencing (ChIP-seq) analysis to identify the molecular network controlled in vivo by Otx2 in RPE cells. We uncover four RPE-specific functions coordinated by Otx2 that underpin the cognate photoreceptor degeneration. Many direct Otx2 target genes are associated with human retinopathies, emphasizing the significance of the model. Importantly, we report a secondary genetic response after Otx2 ablation, which largely precedes apoptosis of Photoreceptors, involving inflammation and stress genes. These findings thus provide novel general markers for clinical detection and prevention of neuronal cell death.
Alexander Samuel - One of the best experts on this subject based on the ideXlab platform.
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loss of otx2 in the adult retina disrupts retinal pigment epithelium function causing photoreceptor degeneration
The Journal of Neuroscience, 2013Co-Authors: Michael Housset, Alexander Samuel, Mohamed Ettaiche, Alexis A Bemelmans, Francis Beby, Nathalie BillonAbstract:Photoreceptors are specialized neurons of the retina that receive nursing from the adjacent retinal pigment epithelium (RPE). Frequent in the elderly, photoreceptor loss can originate from primary dysfunction of either cell type. Despite intense interest in the etiology of these diseases, early molecular actors of late-onset photoreceptor degeneration remain elusive, mostly because of the lack of dedicated models. Conditional Otx2 ablation in the adult mouse retina elicits photoreceptor degeneration, providing a new model of late-onset neuronal disease. Here, we use this model to identify the earliest events after Otx2 ablation. Electroretinography and gene expression analyses suggest a nonautonomous, RPE-dependent origin for photoreceptor degeneration. This is confirmed by RPE-specific ablation of Otx2, which results in similar photoreceptor degeneration. In contrast, constitutive Otx2 expression in RPE cells prevents degeneration of Photoreceptors in Otx2-ablated retinas. We use chromatin immunoprecipitation followed by massive sequencing (ChIP-seq) analysis to identify the molecular network controlled in vivo by Otx2 in RPE cells. We uncover four RPE-specific functions coordinated by Otx2 that underpin the cognate photoreceptor degeneration. Many direct Otx2 target genes are associated with human retinopathies, emphasizing the significance of the model. Importantly, we report a secondary genetic response after Otx2 ablation, which largely precedes apoptosis of Photoreceptors, involving inflammation and stress genes. These findings thus provide novel general markers for clinical detection and prevention of neuronal cell death.
Agnes I Berta - One of the best experts on this subject based on the ideXlab platform.
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photoreceptor cell death proliferation and formation of hybrid rod s cone Photoreceptors in the degenerating stk38l mutant retina
PLOS ONE, 2011Co-Authors: Agnes I Berta, Kathleen Boeszebattaglia, Sem Genini, Orly Goldstein, Paul J Obrien, Agoston Szel, Gregory M Acland, William A Beltran, Gustavo D AguirreAbstract:A homozygous mutation in STK38L in dogs impairs the late phase of photoreceptor development, and is followed by photoreceptor cell death (TUNEL) and proliferation (PCNA, PHH3) events that occur independently in different cells between 7–14 weeks of age. During this period, the outer nuclear layer (ONL) cell number is unchanged. The dividing cells are of photoreceptor origin, have rod opsin labeling, and do not label with markers specific for macrophages/microglia (CD18) or Muller cells (glutamine synthetase, PAX6). Nestin labeling is absent from the ONL although it labels the peripheral retina and ciliary marginal zone equally in normals and mutants. Cell proliferation is associated with increased cyclin A1 and LATS1 mRNA expression, but CRX protein expression is unchanged. Coincident with photoreceptor proliferation is a change in the photoreceptor population. Prior to cell death the photoreceptor mosaic is composed of L/M- and S-cones, and rods. After proliferation, both cone types remain, but the majority of rods are now hybrid Photoreceptors that express rod opsin and, to a lesser extent, cone S-opsin, and lack NR2E3 expression. The hybrid Photoreceptors renew their outer segments diffusely, a characteristic of cones. The results indicate the capacity for terminally differentiated, albeit mutant, Photoreceptors to divide with mutations in this novel retinal degeneration gene.
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Photoreceptor Cell Death, Proliferation and Formation of Hybrid Rod/S-Cone Photoreceptors in the Degenerating STK38L Mutant Retina
PLoS ONE, 2011Co-Authors: Agnes I Berta, Sem Genini, Orly Goldstein, Agoston Szel, Gregory M Acland, William A Beltran, Kathleen Boesze-battaglia, Paul J. O'brien, Gustavo D AguirreAbstract:A homozygous mutation in STK38L in dogs impairs the late phase of photoreceptor development, and is followed by photoreceptor cell death (TUNEL) and proliferation (PCNA, PHH3) events that occur independently in different cells between 7–14 weeks of age. During this period, the outer nuclear layer (ONL) cell number is unchanged. The dividing cells are of photoreceptor origin, have rod opsin labeling, and do not label with markers specific for macrophages/microglia (CD18) or Muller cells (glutamine synthetase, PAX6). Nestin labeling is absent from the ONL although it labels the peripheral retina and ciliary marginal zone equally in normals and mutants. Cell proliferation is associated with increased cyclin A1 and LATS1 mRNA expression, but CRX protein expression is unchanged. Coincident with photoreceptor proliferation is a change in the photoreceptor population. Prior to cell death the photoreceptor mosaic is composed of L/M- and S-cones, and rods. After proliferation, both cone types remain, but the majority of rods are now hybrid Photoreceptors that express rod opsin and, to a lesser extent, cone S-opsin, and lack NR2E3 expression. The hybrid Photoreceptors renew their outer segments diffusely, a characteristic of cones. The results indicate the capacity for terminally differentiated, albeit mutant, Photoreceptors to divide with mutations in this novel retinal degeneration gene.
Seth Blackshaw - One of the best experts on this subject based on the ideXlab platform.
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the orphan nuclear hormone receptor errβ controls rod photoreceptor survival
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Akishi Onishi, Erin M Poth, Uel Alexis, Jimmy De Melo, Jichao Chen, Guanghua Peng, Shiming Chen, Seth BlackshawAbstract:Mutation of rod photoreceptor-enriched transcription factors is a major cause of inherited blindness. We identified the orphan nuclear hormone receptor estrogen-related receptor β (ERRβ) as selectively expressed in rod Photoreceptors. Overexpression of ERRβ induces expression of rod-specific genes in retinas of wild-type as well as Nrl−/− mice, which lack rod Photoreceptors. Mutation of ERRβ results in dysfunction and degeneration of rods, whereas inverse agonists of ERRβ trigger rapid rod degeneration, which is rescued by constitutively active mutants of ERRβ. ERRβ coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in Photoreceptors. Furthermore, enhancing ERRβ activity rescues photoreceptor defects that result from loss of the photoreceptor-specific transcription factor Crx. Our findings demonstrate that ERRβ is a critical regulator of rod photoreceptor function and survival, and suggest that ERRβ agonists may be useful in the treatment of certain retinal dystrophies.
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pias3 dependent sumoylation directs rod photoreceptor development
Neuron, 2009Co-Authors: Akishi Onishi, Uel Alexis, Guanghua Peng, Shiming Chen, Seth BlackshawAbstract:Summary Specification of retinal rod Photoreceptors is determined by several different transcription factors that activate expression of rod-specific genes and repress expression of cone photoreceptor-specific genes. The mechanism by which this dual regulation occurs is unclear. We have found that Pias3, a transcriptional coregulator and E3 SUMO ligase that is selectively expressed in developing Photoreceptors, promotes the differentiation of rod Photoreceptors while preventing rods from adopting cone photoreceptor-like characteristics. Pias3 binds the photoreceptor-specific transcription factors Crx and Nr2e3 and is specifically targeted to the promoters of photoreceptor-specific genes. Pias3 SUMOylates Nr2e3, converting it into a potent repressor of cone-specific gene expression. Rod- and cone-specific promoters are bound by hyperSUMOylated proteins in rod Photoreceptors, and blocking SUMOylation in Photoreceptors results in cells with morphological and molecular features of cones and an absence of rod-specific markers. Our data thus identify Pias3-mediated SUMOylation of photoreceptor-specific transcription factors as a key mechanism of rod specification.
Jonathan Stone - One of the best experts on this subject based on the ideXlab platform.
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photoreceptor dystrophy in the rcs rat roles of oxygen debris and bfgf
Investigative Ophthalmology & Visual Science, 1998Co-Authors: Krisztina Valter, Juliani Maslim, Felicity Bowers, Jonathan StoneAbstract:PURPOSE. To examine the roles of oxygen, basic fibroblast growth factor (bFGF), and photoreceptor debris in the photoreceptor dystrophy of the Royal College of Surgeons (RCS) rat. METHODS. Pups were exposed during the critical period of their development (postnatal day [P] 16-24) and for some days thereafter to hypoxia and hyperoxia. The effects of these exposures on photoreceptor death, debris accumulation in the subretinal space, and the expression of bFGF protein and mRNA by surviving cells were studied. RESULTS. During the critical period hyperoxia slowed photoreceptor death in a dose-related fashion and decreased bFGF protein levels, whereas hypoxia accelerated death and increased bFGF levels. At the edges of the retina, where Photoreceptors survive longest in normoxia, hypoxia had little effect on either photoreceptor death or bFGF protein levels. Oxygen-induced modulation of rates of death could not be related to the accumulation of debris in the subretinal space. After P27, the relationship between oxygen and photoreceptor death changed markedly, hyperoxia no longer delaying and hypoxia no longer accelerating death. CONCLUSIONS. The death of RCS rat Photoreceptors in the period P16 to P27 is precipitated by hypoxia that may result from the accumulation of photoreceptor debris in the subretinal space. This debris, the result of the phagocytotic failure of the retinal pigment epithelium in this strain, lies in the normal pathway of oxygen diffusing to the Photoreceptors from the choriocapillaris. During this period the retina responds to hypoxia by increasing expression of a potentially protective protein (bFGF), but hypoxia-induced damage overwhelms any protection provided by this or other mechanisms. Later stages of the dystrophy may not be hypoxia-induced.
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The Influence of Oxygen on the Survival and Death of Photoreceptors
Degenerative Retinal Diseases, 1997Co-Authors: Krisztina Valter, Juliani Maslim, Kyle Mervin, Jonathan StoneAbstract:We have studied the influence of oxygen on the rates of death of Photoreceptors in the normogenetic mouse and rat, and in the genetically dystrophic RCS rat. Hyperoxia delays photoreceptor death during development of the normogenetic and RCS rats. Hypoxia accelerated photoreceptor death in the adult normogenetic rat and mouse. Hypoxia also accelerates photoreceptor death during development of the normogenetic rat and mouse, and of the RCS rat. The effects of hypoxia were greater in the juvenile, confirming the concept of a critical period in photoreceptor development, during which Photoreceptors are particularly vulnerable to oxygen levels. In the RCS rat, evidence was obtained that the edges of the retina are resistant to hypoxic damage, explaining earlier observations of long-term photoreceptor survival at the edges. It is suggested that nutrient supply is a limiting factor in photoreceptor survival, in both normal and genetically damaged RCS retinas. If these ideas prove relevant also to the human effective therapy for some photoreceptor dystrophies may be achieved by nutrient supplementation.
