Regulation of photoreceptor gene expression by Crx-associated transcription factor network

Hennig, Anne K.; Peng, Guang-Hua; Chen, Shiming

doi:10.1016/j.brainres.2007.06.036

Cited by 184 publications

(185 citation statements)

References 149 publications

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“…The low proportion of Nrl.RFP þ cells in culture ($0.2%) made it impractical to FAC-sort these cells for transplantation. Together these data support the conclusion that photoreceptor precursors are being generated in the ESC cultures, but that rod differentiation may be delayed and that the usual close correspondence in the expression profiles of Crx and Nrl [20,21] is not being recapitulated in vitro.…”

Section: Comparative Analysis Of Photoreceptor Differentiation In Vivsupporting

confidence: 73%

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

West¹,

Gonzalez‐Cordero²,

Hippert³

et al. 2012

Stem Cells

118

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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Section: Comparative Analysis Of Photoreceptor Differentiation In Vivsupporting

confidence: 73%

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

West¹,

Gonzalez‐Cordero²,

Hippert³

et al. 2012

Stem Cells

118

116

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“…For instance, the cone-rod homeobox transcription factor (Crx) is up-regulated during early photoreceptor differentiation and interacts synergistically with retinoid-related orphan nuclear receptors (RORa or RORb) to activate violet/blue (SWS1) opsin transcription in embryonic mice Hennig et al, 2008;Fujieda et al, 2009). Crx also interacts with neural retina leucine zipper (Nrl), a photoreceptor-specific transcription factor that induces rod opsin expression (Chen et al, 1997;Mitton et al, Fig.…”

Section: Developmental Dynamicsmentioning

confidence: 99%

Thyroid hormone accelerates opsin expression during early photoreceptor differentiation and induces opsin switching in differentiated TRα‐expressing cones of the salmonid retina

Gan

Flamarique

2010

Developmental Dynamics

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Thyroid hormone and its receptors (TRs) regulate photoreceptor differentiation and visual pigment protein (opsin) expression in the retinas of several vertebrates, including rodents and fish. In some of these animals, opsin expression can arise through switches within differentiated cone photoreceptors. In salmonid fishes, single cones express ultraviolet (SWS1) opsin during embryonic development and switch to blue (SWS2) opsin as the fishes grow. It is unknown whether thyroid hormone regulates opsin expression during early cone differentiation and acts through TRs to induce opsin switches in differentiated cones of the salmonid retina. Using in situ hybridization, we characterized the spatiotemporal dynamics of opsin expression and switching in embryos treated with exogenous thyroid hormone or propylthiouracil (PTU), a pharmacological inhibitor of thyroid hormone synthesis. We combined immunohistochemistry with in situ hybridization to map TRa expression with respect to cones undergoing the opsin switch in older juvenile fish. Thyroid hormone accelerated opsin expression in differentiating cones and induced the opsin switch in differentiated single cones, whereas PTU repressed the opsin switch. TRa was not detected in differentiating photoreceptors as opsin expression initiated, but was later expressed in differentiated single cones before the onset of the opsin switch. TRa expression exhibited a dynamic dorsoventral distribution that paralleled the progression of the opsin switch. Together, our results show that thyroid hormone is required for opsin switching in the retina of salmonid fishes and suggest that TRa may be involved in regulating this phenomenon. Developmental Dynamics 239:2700-2713,

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“…Photoreceptor subtype-specific opsin expression is regulated by interactions between DNA cis-regulatory elements and a network of photoreceptor transcription factors (5,6). The homeodomain protein cone-rod homeobox (CRX) is required for differentiation and maintenance of both rods and cones (7,8).…”

mentioning

confidence: 99%

Active opsin loci adopt intrachromosomal loops that depend on the photoreceptor transcription factor network

Peng¹,

Chen

2011

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

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Rod and cone opsin genes are expressed in a mutually exclusive manner in their respective photoreceptor subtypes in the mammalian retina. Previous transgenic mouse studies showed that functional interactions between the distal enhancer and proximal promoter of rhodopsin and long/medium-wavelength (L/M) opsin genes are essential for regulating their cell-type-specific transcription. We have used chromosomal conformation capture assays in mouse retinas to investigate the molecular mechanism responsible for this interaction. Here we show that each opsin gene forms intrachromosomal loops in the appropriate photoreceptor subtype, while maintaining a linear configuration in other cell types where it is silent. The enhancer forms physical contacts not only with the promoter but also with the coding regions of each opsin locus. ChIP assays showed that cell-type-specific target binding by three key photoreceptor transcription factors-cone-rod homeobox (CRX), neural retina leucine zipper (NRL), and nuclear receptor subfamily 2, group E, member 3 (NR2E3)-is required for the appropriate local chromosomal organization and transcription of rod and cone opsins. Similar correlations between chromosomal loops and active transcription of opsin genes were also observed in human photoreceptors. Furthermore, quantitative chromosomal conformation capture on human retinas from two male donors showed that the L/M enhancer locus control region (LCR) loops with either the L or M promoter in a near 3:1 ratio, supporting distance-dependent competition between L and M for LCR. Altogether, our results suggest that the photoreceptor transcription factor network cooperatively regulates the chromosomal organization of target genes to precisely control photoreceptor subtypespecific gene expression.neuronal gene expression | enhancer-promoter interaction | chromatin modulation | epigenetic regulation R ods and cones are two types of image-forming photoreceptors that constitute 70% of retinal cells in mice and humans. Rods, representing 95-97% of the photoreceptors, are sensitive to dim light and responsible for night vision. Cones, although constituting only 3-5% of the photoreceptors, sense bright light and mediate color discrimination and visual acuity. These functional differences are attributed, at least in part, to the unique visual pigments made by rods [rhodopsin (Rho)] or cones (cone opsins). Cones can be divided into subtypes based on lightwavelength sensitivity that are characteristically distributed in different species. In humans, cones sensitive to long (L), medium (M), and short (S) wavelengths, each expressing a distinct cone opsin, are enriched within the macular region (1, 2). The mouse retina expresses only two cone opsins, M and S, which are distributed in opposing gradients along the dorsal-ventral axis, forming spatially distinct populations of M, S, and hybrid M/S cones (3, 4).Photoreceptor subtype-specific opsin expression is regulated by interactions between DNA cis-regulatory elements and a network of photoreceptor transc...

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Regulation of photoreceptor gene expression by Crx-associated transcription factor network

Cited by 184 publications

References 149 publications

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

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

Thyroid hormone accelerates opsin expression during early photoreceptor differentiation and induces opsin switching in differentiated TRα‐expressing cones of the salmonid retina

Active opsin loci adopt intrachromosomal loops that depend on the photoreceptor transcription factor network

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