The Rod Photoreceptor-Specific Nuclear Receptor Nr2e3 Represses Transcription of Multiple Cone-Specific Genes

Chen, Jichao; Rattner, Amir; Nathans, Jeremy

doi:10.1523/jneurosci.3571-04.2005

Cited by 238 publications

(290 citation statements)

References 46 publications

Supporting

Mentioning

263

Contrasting

Unclassified

Order By: Relevance

“…c) Direct target gene studies suggest that Nr2e3 is a dual transcription regulator for both rod and cone genes. In vitro protein-DNA binding assays initially showed that Nr2e3 recognizes a consensus DNA sequence with a direct repeat and binds as a homodimer (Kobayashi et al, 1999;Chen et al, 2005). This binding appears to mediate transcriptional repression rather than activation as previously observed for the rhodopsin promoter .…”

Section: Mechanisms Of Actionmentioning

confidence: 66%

“…Expression appears primarily localized to the outer nuclear layer (Kobayashi et al, 1999;Haider et al, 2000;Haider et al, 2001). This persistent expression, mainly in rods in mammals (Bumsted O'Brien et al, 2004;Chen et al, 2005;, suggests that Nr2e3 plays a major role in rod differentiation and maintenance. On the other hand, some early cone precursors appear to transiently express Nr2e3, at least in lower vertebrates and Nr2e3 expression has been reported in other retinal cell types (Chen et al, 1999) including mouse cones [ (Haider et al, 2006); see below], so it may also be involved in other developmental processes.…”

Section: Nr2e3 Is a Dual Transcription Regulator Required For Terminamentioning

confidence: 99%

See 1 more Smart Citation

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

2008

View full text Add to dashboard Cite

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.

show abstract

Section: Mechanisms Of Actionmentioning

confidence: 66%

Section: Nr2e3 Is a Dual Transcription Regulator Required For Terminamentioning

confidence: 99%

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

2008

View full text Add to dashboard Cite

show abstract

“…7). When that pattern was compared with the distribution of PSD95 and SV2, molecules previously shown to be components of photoreceptor synaptic terminals (Chen et al, 2005;Wahlin et al, 2007), clear colocalization was observed (Fig. 7).…”

Section: Subcellular Localization Of Immunoreactivity For Mbnl1 and 2mentioning

confidence: 70%

Developmental regulation of muscleblind‐like (MBNL) gene expression in the chicken embryo retina

Hu¹,

Wahlin²,

McNally³

et al. 2007

Developmental Dynamics

View full text Add to dashboard Cite

Muscleblind-like (MBNL) is a CCCH zinc finger-containing RNA-binding protein required for the development of both muscle and photoreceptors in Drosophila; it is conserved evolutionarily, and it is associated in humans with the muscular disease myotonic dystrophy. Its role in the development of vertebrate retinal cells, however, remains unknown. As an initial approach to its investigation, we have cloned three chick muscleblind genes, characterized their isoforms, and examined their expression patterns in the chick embryo retina. The relative levels of expression of the MBNL genes increased during embryonic development. In situ hybridization (ISH) showed that the three MBNL mRNAs had widespread patterns of expression at all the developmental stages examined. Of interest, the temporal and spatial patterns of protein expression, detected by immunocytochemistry with antibodies against MBNL1 and MBNL2, were much more restricted than those seen by ISH. At early stages (ED5-7), for example, MBNL1 and MBNL2 mRNAs were present throughout the retina, but immunoreactivity for the corresponding proteins was largely restricted to the periphery of the optic cup (presumptive iris/ciliary epithelium/ciliary margin zone). MBNL1 and MBNL2 immunoreactivity became detectable at the fundus at later stages, but was limited to a very small subset of the cells that had ISH signals for the cognate mRNAs (particularly ganglion cells and photoreceptors). Within photoreceptors, MBNL1 and MBNL2 immunoreactivity first appeared in their inner segments; MBNL2 remained there, but MBNL1 became subsequently localized to their synaptic terminals. These expression patterns are consistent with the possibility that MBNLs may regulate photoreceptor development in the chick retina, much as MBL does in Drosophila, and suggest that the expression of MBNL1 and MBNL2 may be regulated posttranscriptionally. Developmental Dynamics 237: 286 -296, 2008.

show abstract

“…NR2E3, also known as PNR and RNR, is an orphan NR expressed exclusively in photoreceptor cells of the adult and developing retina. [6][7][8][9][10][11] The physiological ligand for NR2E3 remains to be identified. Mutations in NR2E3 have been associated with several forms of retinal degeneration in human patients, including enhanced S-cone syndrome, [12][13][14] autosomal dominant 15,16 and recessive 17 forms of retinitis pigmentosa, Goldmann-Favre syndrome, 13 and clumped pigmentary retinal degeneration.…”

Section: Introductionmentioning

confidence: 99%

In Pursuit of Synthetic Modulators for the Orphan Retina-Specific Nuclear Receptor NR2E3

Qin

Knapinska²,

Dobri³

et al. 2013

Journal of Ocular Pharmacology and Therapeutics

View full text Add to dashboard Cite

Purpose: NR2E3 is an orphan nuclear receptor expressed exclusively in photoreceptor cells of the retina. NR2E3-specific modulators may prolong photoreceptor survival in patients with dry age-related macular degeneration and other forms of retinal degeneration. To definitively establish NR2E3 as a photoreceptor protection target, identification of small-molecule NR2E3 modulators and their testing in animal models of retinal degeneration are required. Development of the high-throughput screen (HTS)-compatible screen for small-molecule NR2E3 modulators is the first step toward this goal. Methods: Purification protocol for isolation of the functionally competent soluble NR2E3 protein after its expression in the insect Sf9 cells was developed. The time-resolved fluorescence energy-transfer (TR-FRET) assay assessing agonist-sensitive interaction between apo-NR2E3 and transcriptional corepressor RetCOR was used for characterization of the previously reported putative NR2E3 agonist, Compound 11a, and to conduct the HTS for novel small-molecule NR2E3 modulators (direct and inverse agonists). A counterscreen TR-FRET assay that measures the affect of test compounds on PPARg interaction with corepressor NCOR was used for assessing the specificity of compounds identified in the HTS. Results: We developed the cell-free TR-FRET assay for small-molecule NR2E3 modulators, which is based on agonist-induced disruption of the interaction between GST-tagged apo-NR2E3 and MBP-tagged fragment of transcriptional corepressor RetCOR. Compound 11a, a putative NR2E3 agonist, did not affect the NR2E3-RetCOR interaction, as was established by its titration in the developed assay. The assay was miniaturized for an ultralow-volume 1,536-well format and automated into 3 simple pipetting steps. Consistent with excellent assay performance, the test runs established a Z¢-score within the 0.6-0.8 range. Analysis of the mid-size National Institutes of Health collection of 315,001 structurally diverse drug-like compounds confirmed excellent assay performance, but did not reveal NR2E3-specific agonists or inverse agonists. Conclusions: A robust and reliable TR-FRET assay for small-molecule NR2E3-specific modulators suitable for the analysis of million compound-strong HTS libraries was developed. A previously described putative NR2E3 agonist, Compound 11a, is unlikely to represent a direct NR2E3 agonist. Application of the developed assay for screening of a more abundant and diverse compound collection be required for identification of synthetic NR2E3 ligands.

show abstract

The Rod Photoreceptor-Specific Nuclear Receptor Nr2e3 Represses Transcription of Multiple Cone-Specific Genes

Cited by 238 publications

References 46 publications

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

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

Developmental regulation of muscleblind‐like (MBNL) gene expression in the chicken embryo retina

In Pursuit of Synthetic Modulators for the Orphan Retina-Specific Nuclear Receptor NR2E3

Contact Info

Product

Resources

About