Mutations P51U and G122E in retinal transcription factor NRL associated with autosomal dominant and sporadic retinitis pigmentosa

Martinez-Gimeno, María; Maseras, Miquel; Baiget, Montserrat; Beneito, Magdalena; Antiñolo, G; Ayuso, Carmen; Carballo, Miguel

doi:10.1002/humu.1135

Cited by 40 publications

(40 citation statements)

References 16 publications

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“…This may, in turn, provide a convenient mechanism for precisely fine-tuning the expression of rhodopsin and other rodspecific genes. This hypothesis is consistent with the human mutation reports; 5 of the 6 mutations of NRL, so far reported in patients with autosomal dominant retinitis pigmentosa, are at residues Ser-50 and Pro-51 (27)(28)(29), and the S50T mutation was shown to enhance the ability of NRL to transactivate the rhodopsin promoter in the presence of CRX (27). In addition, the identification of phosphorylation and subsequent mutation analysis of residue Ser-65 in MafA, the homologous residue of Ser-50 in NRL, further supports this hypothesis (58,59).…”

Section: Discussionsupporting

confidence: 89%

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The Minimal Transactivation Domain of the Basic Motif-Leucine Zipper Transcription Factor NRL Interacts with TATA-binding Protein

Friedman

Khanna

Swain

et al. 2004

Journal of Biological Chemistry

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The basic motif-leucine zipper (bZIP) transcription factor NRL controls the expression of rhodopsin and other phototransduction genes and is a key mediator of photoreceptor differentiation. To delineate the molecular mechanisms underlying transcriptional initiation of rod-specific genes, we characterized different regions of the NRL protein using yeast-based autoactivation assays. We identified 35 amino acid residues in the proline-and serine-rich N-terminal region (called minimal transactivation domain, MTD), which, when combined with LexA or Gal4 DNA binding domains, exhibited activation of target promoters. Because this domain is conserved in all proteins of the large Maf family, we hypothesized that NRL-MTD played an important role in assembling the transcription initiation complex. Our studies showed that the NRL protein, including the MTD, interacted with full-length or the C-terminal domain of TATA-binding protein (TBP) in vitro. NRL and TBP could be co-immunoprecipitated from bovine retinal nuclear extract. TBP was also part of c-Maf and MafA (two other large Maf proteins)-containing complex(es) in vivo. Our data suggest that the function of NRL-MTD is to activate transcription by recruiting or stabilizing TBP (and consequently other components of the general transcription complex) at the promoter of target genes, and a similar function may be attributed to other bZIP proteins of the large Maf family.

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Section: Discussionsupporting

confidence: 89%

“…associated with autosomal dominant retinitis pigmentosa (27)(28)(29). In mice, loss of Nrl results in a complete loss of rods and a concomitant increase in functional S-opsin-expressing cones (30).…”

mentioning

confidence: 99%

The Minimal Transactivation Domain of the Basic Motif-Leucine Zipper Transcription Factor NRL Interacts with TATA-binding Protein

Friedman

Khanna

Swain

et al. 2004

Journal of Biological Chemistry

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“…Subsequent mutation analysis of a large pedigree with autosomal dominant retinitis pigmentosa identified a S50T missense mutation in NRL that cosegregates with the disease (Bessant et al, 1999). Although NRL mutations are rare, additional missense mutations linked to adRP have been identified, with hot spots at residues S50 and P51 (Martinez-Gimeno et al, 2001;DeAngelis et al, 2002;Nishiguchi et al, 2004). Some of these hot spot mutations result in mutant forms of NRL that demonstrate reduced phosphorylation but hyperactivity in activating the rhodopsin promoter with CRX in vitro (Bessant et al, 1999;Nishiguchi et al, 2004;Kanda et al, 2007).…”

Section: Human Genetic Studiesmentioning

confidence: 99%

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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“…(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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Mutations P51U and G122E in retinal transcription factor NRL associated with autosomal dominant and sporadic retinitis pigmentosa

Cited by 40 publications

References 16 publications

The Minimal Transactivation Domain of the Basic Motif-Leucine Zipper Transcription Factor NRL Interacts with TATA-binding Protein

The Minimal Transactivation Domain of the Basic Motif-Leucine Zipper Transcription Factor NRL Interacts with TATA-binding Protein

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

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

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