Rod differentiation factor NRL activates the expression of nuclear receptor NR2E3 to suppress the development of cone photoreceptors

Oh, Edwin C.; Cheng, Hong; Hong, Huasheng; Ji, Lin; Khan, Naheed W.; Swaroop, Anand

doi:10.1016/j.brainres.2008.01.028

Cited by 109 publications

(108 citation statements)

References 63 publications

(106 reference statements)

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“…Sumoylation Modulates the Transcriptional Activity of NRL on Rho and Nr2e3 Promoters-We then investigated the effect of K20R, K24R, and K20R/K24R mutations on transcriptional activation of two known photoreceptor-specific target promoters of NRL-rhodopsin (Rho) (32) and Nr2e3 (35). We performed Dual-Luciferase promoter activity assays to compare the transactivation ability of the WT and mutant NRL (either alone or with CRX and NR2E3 (18,23,35)) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Sumoylation of bZIP Transcription Factor NRL Modulates Target Gene Expression during Photoreceptor Differentiation

Roger

Nellissery

Kim³

et al. 2010

Journal of Biological Chemistry

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Development of rod photoreceptors in the mammalian retina is critically dependent on the basic motif-leucine zipper transcription factor NRL (neural retina leucine zipper). In the absence of NRL, photoreceptor precursors in mouse retina produce only cones that primarily express S-opsin. Conversely, ectopic expression of NRL in post-mitotic precursors leads to a rod-only retina. Spatiotemporal control of gene expression is critical for development and homeostasis (1). Cell type-specific expression patterns are established and maintained by transient or stable interactions between cis-regulatory elements in the target genes and trans-regulatory factors that together constitute gene regulatory networks (2). Signaling molecules, another key component of gene regulatory networks, can modify the activity of transcription factors by post-translational modifications (PTMs) 3 such as phosphorylation, acetylation, ubiquitination, and sumoylation (3-6). Rapid and reversible modulation of the activity of transcription factors by PTMs is essential for adaptation to continuously changing cellular microenvironment(s) and is accomplished by altering protein stability, subcellular localization, and protein-DNA and/or protein-protein interaction (3, 6 -8). Consequently, PTMs provide a higher level of control and complexity to gene regulation in a particular biological context. The vertebrate retina exhibits a highly organized laminar structure that captures, integrates, and transmits visual signals to other parts of the central nervous system for further processing. Six neuronal cell types and Muller glia in the retina originate from pools of multipotent progenitor cells in a conserved sequential order (9, 10). The determination of specific cell fate and subsequent differentiation is dictated primarily by intrinsic control mechanisms; however, extrinsic signals modulate key steps in the developmental pathway (9 -13). Rod and cone photoreceptors have a unique and specialized function and initiate the phototransduction process by converting photons into electrical signal (14). Differentiation and homeostasis of photoreceptors are tightly controlled by a set of key transcriptional regulatory proteins, which include nuclear receptors (such as ROR␤ (15), thyroid hormone receptor ␤2 (TR␤2) (16), and NR2E3 (17-21)), homeodomain proteins (such as orthodenticle homeobox 2 (OTX2) (22) and CRX (cone-rod homeobox) (23, 24), signal transducers (including STAT3 (25), PIAS3 (26), glycogen synthase kinase 3 (GSK3) (27)), and NRL, a basic motif-leucine zipper (bZIP) protein of Maf subfamily (28).The bZIP transcription factor NRL is a key regulator of rod versus cone photoreceptor cell fate in mammalian retina (28,29). Targeted deletion of Nrl in mice leads to a retina with only cones that primarily express S-opsin (28), whereas ectopic expression of NRL in photoreceptor precursors leads to a rodonly retina (29). NRL expression is detected soon after the final mitosis and drives a photoreceptor precursor toward rod cell fate (30). NRL interacts wi...

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Section: Resultsmentioning

confidence: 99%

Sumoylation of bZIP Transcription Factor NRL Modulates Target Gene Expression during Photoreceptor Differentiation

Roger

Nellissery

Kim³

et al. 2010

Journal of Biological Chemistry

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“…The experiment was repeated at P28 and P14. Data were compared with data of P28 Nrl Ϫ/Ϫ mice, using a false discovery rate with confidence interval Ͻ0.5 as described (35). Real-time PCR was performed twice on triplicate samples of cDNA made from 2.5 g RNA samples (Ն3 mice/group) using SybrGreen I (Molecular Probes) and iCycler IQ PCR detection (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

Retinoid-related orphan nuclear receptor RORβ is an early-acting factor in rod photoreceptor development

et al. 2009

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

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Rods and cones are morphologically and developmentally distinct photoreceptor types with different functions in vision. Cones mediate daylight and color vision and in most mammals express M and S opsin photopigments for sensitivity to medium-long and short light wavelengths, respectively. Rods mediate dim light vision and express rhodopsin photopigment. The transcription factor networks that direct differentiation of each photoreceptor type are incompletely defined. Here, we report that Rorb ؊/؊ mice lacking retinoid-related orphan nuclear receptor ␤ lose rods but overproduce primitive S cones that lack outer segments. The phenotype reflects pronounced plasticity between rod and cone lineages and resembles that described for Nrl ؊/؊ mice lacking neural retina leucine zipper factor. Rorb ؊/؊ mice lack Nrl expression and reexpression of Nrl in Rorb ؊/؊ mice converts cones to rod-like cells. Thus, Rorb directs rod development and does so at least in part by inducing the Nrl-mediated pathway of rod differentiation.cone ͉ differentiation R ods and cones are distinct receptor cell types that mediate dim and bright light vision, respectively. In the mouse, cones are generated between midgestation and birth (1) and subpopulations differentially express M and S opsin photopigments for sensitivity to medium-long and short light wavelengths, respectively (2). Rods express rhodopsin and greatly outnumber cones in mice. Rod generation lags behind that of cones and is more protracted, lasting until about a week after birth. Rods, cones, and other retinal cell types are generated in a stereotypical order from multipotent progenitors, and it has been proposed that a combination of transcription factor activities and external signals at a given developmental stage prompts progenitors to enter specific differentiation pathways (3, 4).The transcription factors that direct the generation of rod and cone precursors and the terminal differentiation of these cell types are incompletely defined. During terminal differentiation of cones, thyroid hormone receptor TR␤2 is required for M opsin induction such that without TR␤2, cones express only S opsin (5). Factors that promote rod differentiation and survival include leucine zipper protein Nrl (6), orphan nuclear receptor Nr2e3 (7, 8), homeodomain proteins Crx and Otx2 (9-11), and retinoblastoma protein Rb (12,13). Nrl induces Nr2e3 expression and these two genes define a transcriptional hierarchy for rod differentiation. Nrl Ϫ/Ϫ mice overproduce S cones at the expense of rods (6) whereas ectopic Nrl expression converts cones to rods (14). Nr2e3 deficiency causes an enhanced cone phenotype and misexpression of cone genes in rods, suggesting that Nr2e3 represses cone genes to maintain the rod phenotype (15-19). Human NRL and NR2E3 mutations result in retinopathy phenotypes (8,20). The above findings suggest that rod and cone precursors share a default differentiation program as cones and that rod differentiation requires the action of additional transcription factors.The Rorb gene encodin...

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“…The expression of the neural retina basic motif-leucine zipper transcription factor (NRL; MIM] 162080) starts at E14.5 and determines the rod lineage [Liu et al, 1996;Mears et al, 2001]. NRL binds to an enhancer region of the Nr2e3 gene and activates transcription in synergism with CRX [Oh et al, 2008]. Nr2e3 transcripts start to be detected at E16.5 and peak at postnatal day 6 (P6), concomitant with the onset of rhodopsin expression Oh et al, 2008].…”

Section: Introductionmentioning

confidence: 99%

“…NRL binds to an enhancer region of the Nr2e3 gene and activates transcription in synergism with CRX [Oh et al, 2008]. Nr2e3 transcripts start to be detected at E16.5 and peak at postnatal day 6 (P6), concomitant with the onset of rhodopsin expression Oh et al, 2008]. In the absence of NR2E3, an about two-fold increase in short wavelength-sensitive (S)-opsin (Opn1sw) expressing cones (''blue'' cones) is observed, indicating that NR2E3 acts as a suppressor of the cone generation program in late mitotic retinal progenitor cells [Haider et al, 2001[Haider et al, , 2006.…”

Section: Introductionmentioning

confidence: 99%

NR2E3mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP)

Schorderet

Escher

2009

Hum. Mutat.

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NR2E3, also called photoreceptor-specific nuclear receptor (PNR), is a transcription factor of the nuclear hormone receptor superfamily whose expression is uniquely restricted to photoreceptors. There, its physiological activity is essential for proper rod and cone photoreceptor development and maintenance. Thirtytwo different mutations in NR2E3 have been identified in either homozygous or compound heterozygous state in the recessively inherited enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD). The clinical phenotype common to all these patients is night blindness, rudimental or absent rod function, and hyperfunction of the ''blue'' S-cones. A single p.G56R mutation is inherited in a dominant manner and causes retinitis pigmentosa (RP). We have established a new locus-specific database for NR2E3 (www.LOVD.nl/eye), containing all reported mutations, polymorphisms, and unclassified sequence variants, including novel ones. A high proportion of mutations are located in the evolutionarily-conserved DNA-binding domains (DBDs) and ligand-binding domains (LBDs) of NR2E3. Based on homology modeling of these NR2E3 domains, we propose a structural localization of mutated residues. The high variability of clinical phenotypes observed in patients affected by NR2E3-linked retinal degenerations may be caused by different disease mechanisms, including absence of DNA-binding, altered interactions with transcriptional coregulators, and differential activity of modifier genes.

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Rod differentiation factor NRL activates the expression of nuclear receptor NR2E3 to suppress the development of cone photoreceptors

Cited by 109 publications

References 63 publications

Sumoylation of bZIP Transcription Factor NRL Modulates Target Gene Expression during Photoreceptor Differentiation

Sumoylation of bZIP Transcription Factor NRL Modulates Target Gene Expression during Photoreceptor Differentiation

Retinoid-related orphan nuclear receptor RORβ is an early-acting factor in rod photoreceptor development

NR2E3mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP)

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