Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina

Jelcick, Austin S.; Yuan, Ye; Leehy, Barrett; Cox, Lakeisha C.; Silveira, Alexandra C.; Qiu, Fang; Schenk, Sarah; Sachs, Andrew J.; Morrison, Margaux A.; Nystuen, Arne; DeAngelis, Margaret M.; Haider, Neena B.

doi:10.1371/journal.pone.0021858

Cited by 28 publications

(34 citation statements)

References 65 publications

(57 reference statements)

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“…These time points were chosen to represent miRNAs important in development when Nr2e3 is first expressed, and those miRNAs important to maintain normal function in the mature retina. Potential miRNA target genes at each of the two time points were then cross-referenced to microarray expression data 91 . To identify differentially expressed miRNA potential target genes showing biological significance, miRNA target genes were cross-referenced with microarray data mentioned above (GSE24512) and those exhibiting greater than 2-fold change of gene expression in Nr2e3 rd7 / rd7 when compared to C57BL6 / J mice were further analyzed.…”

Section: Resultsmentioning

confidence: 99%

Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina

Olivares

Jelcick

Reinecke

et al. 2017

Sci Rep

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Regulation of biological processes occurs through complex, synergistic mechanisms. In this study, we discovered the synergistic orchestration of multiple mechanisms regulating the normal and diseased state (age related macular degeneration, AMD) in the retina. We uncovered gene networks with overlapping feedback loops that are modulated by nuclear hormone receptors (NHR), miRNAs, and epigenetic factors. We utilized a comprehensive filtering and pathway analysis strategy comparing miRNA and microarray data between three mouse models and human donor eyes (normal and AMD). The mouse models lack key NHRS (Nr2e3, RORA) or epigenetic (Ezh2) factors. Fifty-four total miRNAs were differentially expressed, potentially targeting over 150 genes in 18 major representative networks including angiogenesis, metabolism, and immunity. We identified sixty-eight genes and 5 miRNAS directly regulated by NR2E3 and/or RORA. After a comprehensive analysis, we discovered multimodal regulation by miRNA, NHRs, and epigenetic factors of three miRNAs (miR-466, miR1187, and miR-710) and two genes (Ell2 and Entpd1) that are also associated with AMD. These studies provide insight into the complex, dynamic modulation of gene networks as well as their impact on human disease, and provide novel data for the development of innovative and more effective therapeutics.

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Section: Resultsmentioning

confidence: 99%

Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina

Olivares

Jelcick

Reinecke

et al. 2017

Sci Rep

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“…Phenotypic variability based on genetic background differences observed in mice (28,29) can provide models for complex human conditions and explain the variable susceptibility to certain conditions among different individuals with the same allelic variant of disease. With no reliable markers to date for ARD before it becomes clinically evident, genetic studies have involved only affected individuals, making it difficult to identify factors that trigger this condition.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory priming predisposes mice to age-related retinal degeneration

Mustafi¹,

Maeda²,

Kohno³

et al. 2012

J. Clin. Invest.

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Disruption of cellular processes affected by multiple genes and accumulation of numerous insults throughout life dictate the progression of age-related disorders, but their complex etiology is poorly understood. Postmitotic neurons, such as photoreceptor cells in the retina and epithelial cells in the adjacent retinal pigmented epithelium, are especially susceptible to cellular senescence, which contributes to age-related retinal degeneration (ARD). The multigenic and complex etiology of ARD in humans is reflected by the relative paucity of effective compounds for its early prevention and treatment. To understand the genetic differences that drive ARD pathogenesis, we studied A/J mice, which develop ARD more pronounced than that in other inbred mouse models. Although our investigation of consomic strains failed to identify a chromosome associated with the observed retinal deterioration, pathway analysis of RNA-Seq data from young mice prior to retinal pathological changes revealed that increased vulnerability to ARD in A/J mice was due to initially high levels of inflammatory factors and low levels of homeostatic neuroprotective factors. The genetic signatures of an uncompensated preinflammatory state and ARD progression identified here aid in understanding the susceptible genetic loci that underlie pathogenic mechanisms of age-associated disorders, including several human blinding diseases. IntroductionAge-related disorders arise from failure of tissue maintenance and repair pathways that are accelerated by certain inherited and acquired factors (1). Long-lived nondividing cells, such as neurons, have markedly reduced tolerance to damage (2), and thus exhibit the most pronounced age-related changes. Neuronal cells in the retina are an especially attractive model system to study this phenomenon, owing to their accessibility and wellunderstood physiology. Rod and cone photoreceptors are retinal neuronal cells that initiate visual perception, a function requiring a competent neighboring retinal pigmented epithelium (RPE) for their normal operation (3). In postmitotic cells such as these photoreceptor and RPE cells, cellular senescence can ensue when shed oxidized photoreceptor outer segments (POS) are inadequately phagocytosed and digested by the RPE. This results in accumulation of damaged proteins, formation of toxic metabolic byproducts, inflammatory cell invasion, and cell death. RPE cells are the most affected because, in addition to processing POS, they serve as the conduit between photoreceptors and the choroidal blood supply for metabolite exchange (4). Acquisition of senescence-associated pathology stimulates cells to secrete various factors that contribute to tissue dysfunction. Conversely, adequate clearance of such cells can delay the onset of age-related tissue pathology (5).Aging laboratory experimental animals are important models for studying age-related pathology, especially neurodegenerative disorders, which have been shown to be affected by their genetic backgrounds (6, 7). The A/J inbred mouse ...

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“…The numbers of specific types of cells in the retina as measured by histology, is partly determined by cell fate, which is strongly related to genetics and species differences (Jelcick, Yuan, & Leehy et al, 2011; Whitney, Raven, & Ciobanu et al, 2011). Other developmental factors may influence retinal neural cell numbers, such as the prenatal environment including exposure to light (Rao, Chan, & Fun et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Distribution differences of macular cones measured by AOSLO: Variation in slope from fovea to periphery more pronounced than differences in total cones

et al. 2017

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Large individual differences in cone densities occur even in healthy, young adults with low refractive error. We investigated whether cone density follows a simple model that some individuals have more cones, or whether individuals differ in both number and distribution of cones. We quantified cones in the eyes of 36 healthy young adults with low refractive error using a custom adaptive optics scanning laser ophthalmoscope. The average cone density in the temporal meridian was, for the mean ± SD, 43216 ± 6039, 27466 ± 3496, 14996 ± 1563, and 12207 ± 1278 cones /mm2 for 270, 630, 1480, and 2070 microns from the foveal center. Cone densities at 630 microns retinal eccentricity were uncorrelated to those at 2070 microns, ruling out models with a constant or proportional relation of cone density to eccentricity. Subjects with high central macula cone densities had low peripheral cone densities. The cone density ratio (2070 : 630 microns) was negatively correlated with cone density at 630 microns, consistent with variations in the proportion of peripheral cones migrating towards the center. We modelled the total cones within a central radius of 7 deg, using the temporal data and our published cone densities for temporal, nasal, superior, and inferior meridians. We computed an average of 221,000 cones. The coefficient of variation was 0.0767 for total cones, but higher for samples near the fovea. Individual differences occur both in total cones and other developmental factors related to cone distribution.

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Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina

Cited by 28 publications

References 65 publications

Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina

Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina

Inflammatory priming predisposes mice to age-related retinal degeneration

Distribution differences of macular cones measured by AOSLO: Variation in slope from fovea to periphery more pronounced than differences in total cones

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