Cone-like Morphological, Molecular, and Electrophysiological Features of the Photoreceptors of the<i>Nrl</i>Knockout Mouse

Daniele, Lauren L.; Lillo, Concepción; Lyubarsky, Arkady; Nikonov, Sergei; Philp, Nancy J.; Mears, Alan J.; Swaroop, Anand; Williams, David S.; Pugh, Edward N.

doi:10.1167/iovs.04-1427

Cited by 188 publications

(253 citation statements)

References 65 publications

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“…Although the dorsal/ventral M/S-cone gradient is preserved in Nrl −/− mice, more S-opsin sensitivity is seen in Nrl −/− cones than in wild-type cones from comparable dorsal/ventral levels of the retina (Nikonov et al, 2006). Consistent with the above electrophysiological measures, the ultrastructural analysis showed that the Nrl −/− retina has much shorter cone-like outer segments with disrupted morphology and cone-like nuclei with decondensed chromatin Daniele et al, 2005). Whorls and rosettes are seen at early ages and thinning of the outer nuclear layer occurs later on , similar to retinal histopathology in rd7 mice.…”

Section: Animal Studiessupporting

confidence: 66%

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: Animal Studiessupporting

confidence: 66%

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

2008

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“…[24][25][26][27] In the retina of Nrl knockout mice, Fischer et al 24 show that the histology of rosette structures corresponds with the round or ovoid features with highly reflective annular lines observed in speckle noise-reduced SD-OCT. Although it remains unclear whether the rosettes in animal models are same as the ORT in human patients, 26 this correspondence suggests that the ORT is comprised of rearranged neuronal cells.…”

Section: Discussionmentioning

confidence: 99%

Tomographic fundus features in pseudoxanthoma elasticum: comparison with neovascular age-related macular degeneration in Japanese patients

Ellabban

Hangai

Yamashiro

et al. 2012

Eye

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Purpose To determine the retinal and subretinal features characteristic to pseudoxanthoma elasticum (PXE) compared with age-related macular degeneration by using spectral-domain optical coherence tomography (SD-OCT) in Japanese patients. Methods We reviewed colour fundus photographs, fluorescein angiograms, and SD-OCT images of 52 eyes (27 Japanese patients) with angioid streaks (AS) due to PXE. Then we compared the incidence of tomographic features between 24 eyes (24 patient) with choroidal neovascularization (CNV) secondary to AS and 44 eyes (44 patients) with CNV secondary to age-related macular degeneration (AMD). Results Secondary CNV was found in 44 eyes (84.6%) of 52 patients with PXE during follow-up. We found characteristic round or ovoid tubular structures with highly reflective annular lines (termed 'outer retinal tubulation' (ORT)) in 31 (70.5%) of 44 eyes with CNV, but none were found in eyes without CNV. We also found characteristic undulations of Bruch's membrane in 38 (73.1%) eyes with AS. The incidence of ORT was significantly greater in eyes with CNV secondary to AS (70.8%; P ¼ 0.005) compared with eyes with CNV secondary to AMD (34.1%). The incidence of Bruch's membrane undulation was significantly greater in eyes with CNV secondary to AS (70.8%; Po0.0001) than in eyes with CNV secondary to AMD (11.4%).Conclusion SD-OCT imaging clearly revealed a greater incidence of unique lesions, including ORT and Bruch's membrane undulation, in eyes in PXE patients with CNV secondary to AS than in eyes with CNV secondary to AMD.

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“…In the absence of the transcription factor NRL, rod progenitor cells divert to an S-cone-like phenotype. Thus, the nrl 2/2 retina is made up of a small number of 'authentic' S-and M-cones and a large number of S-cone-like cells which do not exhibit precisely native S-cone behavior (7,8). In addition, although it is well established that the cone opsin promoter we used drives COP-T expression in S-and M-cones, it originates from the M-opsin gene and the levels of expression in M-versus S-cones have not been quantified.…”

Section: Discussionmentioning

confidence: 99%

Differences in RDS trafficking, assembly and function in cones versus rods: insights from studies of C150S-RDS

Chakraborty

Conley

Stuck

et al. 2010

Human Molecular Genetics

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Cysteine 150 of retinal degeneration slow protein (RDS) mediates the intermolecular disulfide bonding necessary for large RDS complex assembly and morphogenesis of the rim region of photoreceptor outer segments. Previously, we showed that cones have a different requirement for RDS than rods, but the nature of that difference was unclear. Here, we express oligomerization-incompetent RDS (C150S-RDS) in the conedominant nrl 2/2 mouse. Expression of C150S-RDS leads to dominant functional abnormalities, ultrastructural changes, biochemical anomalies and protein mislocalization in cones. These data suggest that RDS complexes in cones are more susceptible to disruption than those in rods, possibly due to structural or microenvironmental differences in the two cell types. Furthermore, our results suggest that RDS intermolecular disulfide bonding may be part of RDS inner-segment assembly in cones but not in rods. These data highlight significant differences in assembly, trafficking and function of RDS in rods versus cones.

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Cone-like Morphological, Molecular, and Electrophysiological Features of the Photoreceptors of theNrlKnockout Mouse

Abstract: Many morphological, molecular, and electrophysiological features of the Nrl(-/-) photoreceptors are cone-like, and strongly distinguish these cells from rods. This retina provides a model for the investigation of cone function and cone-specific genetic disease.

Cited by 188 publications

References 65 publications

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

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

Tomographic fundus features in pseudoxanthoma elasticum: comparison with neovascular age-related macular degeneration in Japanese patients

Differences in RDS trafficking, assembly and function in cones versus rods: insights from studies of C150S-RDS

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