A thyroid hormone receptor that is required for the development of green cone photoreceptors

Ng, Lily; Hurley, James B.; Dierks, Blair; Srinivas, Maya; Saltó, Carmen; Vennström, Björn; Reh, Thomas A.; Forrest, Douglas

doi:10.1038/83829

Cited by 498 publications

(514 citation statements)

References 26 publications

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“…The thyroid hormone receptor Trβ2, a splice variant of the thyroid hormone receptor B (Thrb) gene, is implicated in photoreceptor development in chick and mouse, based on its expression in retinal progenitor cells and developing photoreceptors. In mouse eyes, expression of Trβ2 begins about E16, peaks around E18 as cone photoreceptors begin differentiating, then decreases (Ng et al, 2001;Yanagi et al, 2002), but the expression is uniform across the retina (Ng et al, 2001;Roberts et al, 2005;Roberts et al, 2006). However, during the time M-cones are developing, its ligand TH becomes distributed in a gradient with higher concentrations in the dorsal than ventral retina [ (Roberts et al, 2006); Figure 2B].…”

Section: Trβ2 Is a Positive Regulator For M-conesmentioning

confidence: 99%

“…These results showed that Trβ2 induced M-opsin expression and concurrently inhibited S-cone production in a ligand-dependent manner. Knockout of the photoreceptor-specific Trβ2 isoform of the Thrb gene converted all cones to the S-phenotype, resulting in loss of both M-opsin expression and the S-cone gradient in vivo (Ng et al, 2001). This phenotype is also reproduced in a mouse with a knockin mutation in the DNA binding domain of Thrb that abolishes specific DNA sequence binding without affecting ligand binding or cofactor interactions (Shibusawa et al, 2003).…”

Section: Trβ2 Is a Positive Regulator For M-conesmentioning

confidence: 99%

“…The cone transcription factor Trβ2 binds to both M-opsin and S-opsin promoters in WT retinae (Figure 3 "Trβ2" panel) to activate M-opsin but repress S-opsin expression (Ng et al, 2001;Yanagi et al, 2002). Trβ2 also binds to the rhodopsin promoter (Figure 3) and several other rod genes (data not shown) in a Crx-dependent manner, suggesting that it could also be involved in regulating (likely repressing) the expression of rod genes in cone cells.…”

Section: Photoreceptor Transcription Factors Form a Network To Regulamentioning

confidence: 99%

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

2008

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Rod and cone photoreceptors in the mammalian retina are special types of neurons that are responsible for phototransduction, the first step of vision. Development and maintenance of photoreceptors require precisely regulated gene expression. This regulation is mediated by a network of photoreceptor transcription factors centered on Crx, an Otx-like homeodomain transcription factor. The cell type (subtype) specificity of this network is governed by factors that are preferentially expressed by rods or cones or both, including the rod-determining factors neural retina leucine zipper protein (Nrl) and the orphan nuclear receptor Nr2e3; and cone-determining factors, mostly nuclear receptor family members. The best-documented of these include thyroid hormone receptor β2 (Trβ2), retinoid related orphan receptor Rorβ, and retinoid X receptor Rxrγ. The appropriate function of this network also depends on general transcription factors and co-factors that are ubiquitously expressed, such as the Sp zinc finger transcription factors and STAGA coactivator complexes. These cell type-specific and general transcription regulators form complex interactomes; mutations that interfere with any of the interactions can cause photoreceptor development defects or degeneration. In this manuscript, we review recent progress on the roles of various photoreceptor transcription factors and interactions in photoreceptor subtype development. We also provide evidence of auto-, para-, and feedback regulation among these factors at the transcriptional level. These protein-protein and protein-promoter interactions provide precision and specificity in controlling photoreceptor subtype-specific gene expression, development and survival. Understanding these interactions may provide insights to more effective therapeutic interventions for photoreceptor diseases.

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Section: Trβ2 Is a Positive Regulator For M-conesmentioning

confidence: 99%

Section: Trβ2 Is a Positive Regulator For M-conesmentioning

confidence: 99%

Section: Photoreceptor Transcription Factors Form a Network To Regulamentioning

confidence: 99%

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

2008

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“…In mice, at least two nuclear receptor isoforms, TR␤1 and TR␤2, are encoded by a TR␤ gene locus. When the TR␤2 isoform is deleted, S opsin repression in the dorsal cones is lost and M opsin transcription is abolished in all cones (Ng et al, 2001;Shibusawa et al, 2003). S opsin is transcribed early during the embryonic period in mouse and humans, but M opsin is expressed days or weeks later as the cone cell matures (Szél et al, 1993;Chen et al, 1994;Xiao and Hendrickson, 2000;Cornish et al, 2004a).…”

Section: Introductionmentioning

confidence: 99%

Transient expression of thyroid hormone nuclear receptor TRβ2 sets S opsin patterning during cone photoreceptor genesis

Applebury

Farhangfar

Glösmann

et al. 2007

Developmental Dynamics

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Cone photoreceptors in the murine retina are patterned by dorsal repression and ventral activation of S opsin. TR␤2, the nuclear thyroid hormone receptor ␤ isoform 2, regulates dorsal repression. To determine the molecular mechanism by which TR␤2 acts, we compared the spatiotemporal expression of TR␤2 and S opsin from embryonic day (E) 13 through adulthood in C57BL/6 retinae. TR␤2 and S opsin are expressed in cone photoreceptors only. Both are transcribed by E13, and their levels increase with cone genesis. TR␤2 is expressed uniformly, but transiently, across the retina. mRNA levels are maximal by E17 at completion of cone genesis and again minimal before P5. S opsin is also transcribed by E13, but only in ventral cones. Repression in dorsal cones is established by E17, consistent with the occurrence of patterning during cone cell genesis. The uniform expression of TR␤2 suggests that repression of S opsin requires other dorsalspecific factors in addition to TR␤2. The mechanism by which TR␤2 functions was probed in transgenic animals with TR␤2 ablated, TR␤2 that is DNA binding defective, and TR␤2 that is ligand binding defective. These studies show that TR␤2 is necessary for dorsal repression, but not ventral activation of S opsin. TR␤2 must bind DNA and the ligand T3 (thyroid hormone) to repress S opsin. Once repression is established, T3 no longer regulates dorsal S opsin repression in adult animals. The transient, embryonic action of TR␤2 is consistent with a role (direct and/or indirect) in chromatin remodeling that leads to permanent gene silencing in terminally differentiated, dorsal cone photoreceptors.

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“…(Akagi, et al, 2004, Brown, et al, 1998, Brown, et al, 2001, Hojo, et al, 2000, Kanekar, et al, 1997, Marquardt and Gruss, 2002, Moore, et al, 2002, Morrow, et al, 1999, Yan and Wang, 1998 Several transcription factors are clearly essential for photoreceptor development, and their mutations cause retinal degenerations: NRL, CRX, Otx2, Trβ2 (thyroid hormone receptor β2), and NR2E3. (Bessant, et al, 1999, DeAngelis, et al, 2002, Freund, et al, 1997, Haider, et al, 2000, Haider, et al, 2001, Martinez-Gimeno, et al, 2001, Ng, et al, 2001, Nishida, et al, 2003, Swain, et al, 1997 However, our knowledge of the interactions of these cell-specific proteins with each other and upstream signal transduction proteins remains sparse. We do not know how this pool of cell-specific transcription factors interacts with the pool of ubiquitous proteins, which include the general transcription machinery and epigenetic regulators of chromatin/DNA structure.…”

Section: Introductionmentioning

confidence: 99%

FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro

Mali

Zhang

Hoerauf

et al. 2007

Experimental Eye Research

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FIZ1 (Flt-3 Interacting Zinc-finger) interacts and co-purifies with the rod-specific transcription factor NRL (Neural Retina Leucine zipper). We hypothesize that FIZ1 is part of an interface between cell-specific factors, like NRL, and more ubiquitous regulatory networks that vary the absolute expression levels of some rod-specific genes (i.e. Rhodopsin). As part of an ongoing exploration of FIZ1's role in neural retina, in vivo, we have taken the first look at FIZ1 expression in the developing mouse retina during the retinal maturation period. Using the normal C57/B6 mouse as a model, multiple approaches were used including: immunoblotting, immunohistochemistry, and quantitative real-time PCR. Functional implications of FIZ1/NRL interaction, on NRL-and CRX-mediated activation of the Rhodopsin (Rho) and cGMPphosphodiesterase β-subunit gene (PDE6B) promoters, were examined by co-transfection assays. Immunoblot analysis revealed that FIZ1 protein levels were lowest in immature mouse neural retina (P0). FIZ1 concentration increased at least ten-fold as the neural retina matured to the adult state (P21 and later). Immunohistochemical comparison of immature post-natal and mature adult retina revealed increasing FIZ1 protein in photoreceptors, the inner plexiform layer, and the ganglion cell layer. Total retinal Fiz1 mRNA content increased as the neural retina matured. The expected increase in Rho mRNA level was also monitored as a genetic marker of photoreceptor maturation. In transient co-transfection assays of CV1 cells, FIZ1 synergized with NRL to activate transcription from the Rho and PDE6B gene promoters with some differences. In the case of the Rho promoter, FIZ1 synergized when both NRL and CRX were present. With the PDE6B promoter, FIZ1 synergized with NRL alone, and the inclusion of CRX decreased this synergy.Conclusions-These findings support previous evidence that FIZ1 is present in rodphotoreceptors. (Co-immunoprecipitation from nuclear-protein extracts with rod-specific NRL) FIZ1 expression increases in the neural retina during the retinal maturation period. Additionally, in vitro experiments demonstrate that FIZ1 has the potential to significantly increase the NRLmediated activation of photoreceptor-specific promoters. While CRX is not a strong activator of the PDE6B promoter, alone or with NRL, CRX decreased the synergy of NRL with FIZ1.

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A thyroid hormone receptor that is required for the development of green cone photoreceptors

Cited by 498 publications

References 26 publications

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

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

Transient expression of thyroid hormone nuclear receptor TRβ2 sets S opsin patterning during cone photoreceptor genesis

FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro

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