Induction of Functional Photoreceptor Phenotype by Exogenous<i>Crx</i>Expression in Mouse Retinal Stem Cells

Jomary, Catherine; Jones, Stephen E.

doi:10.1167/iovs.07-0812

Cited by 26 publications

(29 citation statements)

References 64 publications

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“…Crxa induces retinal stem cells to differentiate into functional photoreceptors44. When knocked down in zebrafish, crxa prompts the downregulation of genes in the phototransduction cascade45, and is implicated in eye reduction experienced by another troglomorphic fish, Sinocyclocheilus anophtalmus 46.…”

Section: Resultsmentioning

confidence: 99%

The cavefish genome reveals candidate genes for eye loss

et al. 2014

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Natural populations subjected to strong environmental selection pressures offer a window into the genetic underpinnings of evolutionary change. Cavefish populations, Astyanax mexicanus (Teleostei: Characiphysi), exhibit repeated, independent evolution for a variety of traits including eye degeneration, pigment loss, increased size and number of taste buds and mechanosensory organs, and shifts in many behavioural traits. Surface and cave forms are interfertile making this system amenable to genetic interrogation; however, lack of a reference genome has hampered efforts to identify genes responsible for changes in cave forms of A. mexicanus. Here we present the first de novo genome assembly for Astyanax mexicanus cavefish, contrast repeat elements to other teleost genomes, identify candidate genes underlying quantitative trait loci (QTL), and assay these candidate genes for potential functional and expression differences. We expect the cavefish genome to advance understanding of the evolutionary process, as well as, analogous human disease including retinal dysfunction.

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Section: Resultsmentioning

confidence: 99%

The cavefish genome reveals candidate genes for eye loss

et al. 2014

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“…Specifically: (a) both YAP1 and CD133, NANOG and OCT-3/4 stem cell markers are overexpressed in HCC, and their expression is higher in more aggressive tumors exhibiting higher growth rate and lower apoptosis; (b) NANOG and OCT-3/4 protein levels are statistically correlated with YAP1 and YAP1-TEAD levels in HCC; (c) forced YAP1 overexpression in liver tumor cell lines induces consistent increase of CD133, NANOG and OCT-3/4 expression, cell viability, migration and invasivity, whereas YAP1 inhibition by specific siRNA leads to opposite changes; (d) stem cell markers overexpression does not occur in cancer cell lines transfected with mutant YAP1 that does not form complexes with TEAD [23]. Remarkably, microarray analysis showed that forced YAP1 overexpression in Huh7 cells resulted in increased expression of genes that mediate the acquisition of a stem cells phenotype in cancer of liver and/or other tissues, including MAP2K5 [32, 33] , PPM1A [34], PTPN11 [35], PTPRM [36], PDE2A [37] IRF2 [38], LDHA [39] SH3KBP1 [40] and SPSB1 [41]. Interestingly, the expression of MAP2K5, PPM1A, PTPN11, and SPSB1 revealed a sharp increase especially in more aggressive HCCP exhibiting highest expression of stem cell markers, as well as in HepG2 cells transfected with YAP1.…”

Section: Discussionmentioning

confidence: 99%

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

et al. 2016

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Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14–3–3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells.

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“…This process occurs through release of the α-transducin subunit, which can activate the cGMP phosphodiesterase, ultimately resulting in membrane hyperpolarization (Michaelides et al, 2006). To establish if cells could degrade cGMP in response to light exposure, we measured cGMP levels by immunoassay in cells differentiated for 35 days in NDI or CI medium (Jomary and Jones, 2008). Extracts were isolated from cells exposed to a bright light for 1 min or maintained in the dark for 2 days.…”

Section: Cone Phenotype and Cgmp Degradation In Vitromentioning

confidence: 99%

Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFβ and Wnt signaling

et al. 2015

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Cone photoreceptors are required for color discrimination and highresolution central vision and are lost in macular degenerations, cone and cone/rod dystrophies. Cone transplantation could represent a therapeutic solution. However, an abundant source of human cones remains difficult to obtain. Work performed in model organisms suggests that anterior neural cell fate is induced 'by default' if BMP, TGFβ and Wnt activities are blocked, and that photoreceptor genesis operates through an S-cone default pathway. We report here that Coco (Dand5), a member of the Cerberus gene family, is expressed in the developing and adult mouse retina. Upon exposure to recombinant COCO, human embryonic stem cells (hESCs) differentiated into S-cone photoreceptors, developed an inner segment-like protrusion, and could degrade cGMP when exposed to light. Addition of thyroid hormone resulted in a transition from a unique S-cone population toward a mixed M/S-cone population. When cultured at confluence for a prolonged period of time, COCOexposed hESCs spontaneously developed into a cellular sheet composed of polarized cone photoreceptors. COCO showed dosedependent and synergistic activity with IGF1 at blocking BMP/TGFβ/ Wnt signaling, while its cone-inducing activity was blocked in a dosedependent manner by exposure to BMP, TGFβ or Wnt-related proteins. Our work thus provides a unique platform to produce human cones for developmental, biochemical and therapeutic studies and supports the hypothesis that photoreceptor differentiation operates through an S-cone default pathway during human retinal development.

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Induction of Functional Photoreceptor Phenotype by ExogenousCrxExpression in Mouse Retinal Stem Cells

Cited by 26 publications

References 64 publications

The cavefish genome reveals candidate genes for eye loss

The cavefish genome reveals candidate genes for eye loss

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFβ and Wnt signaling

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