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Gene expression signatures in tree shrew choroid in response to three myopiagenic conditions.

ABSTRACT: We examined gene expression in tree shrew choroid in response to three different myopiagenic conditions: minus lens (ML) wear, form deprivation (FD), and continuous darkness (DK). Four groups of tree shrews (n=7 per group) were used. Starting 24 days after normal eye opening (days of visual experience [DVE]), the ML group wore a monocular -5D lens for 2 days. The FD group wore a monocular translucent diffuser for 2 days. The DK group experienced continuous darkness binocularly for 11 days, starting at 17 DVE. An age-matched normal group was examined at 26 DVE. Quantitative PCR was used to measure the relative (treated eye vs. control eye) differences in mRNA levels in the choroid for 77 candidate genes. Small myopic changes were observed in the treated eyes (relative to the control eyes) of the ML group (-1.0±0.2D; mean±SEM) and FD group (-1.9±0.2D). A larger myopia developed in the DK group (-4.4±1.0D) relative to Normal eyes (both groups, mean of right and left eyes). In the ML group, 28 genes showed significant differential mRNA expression; eighteen were down-regulated. A very similar pattern occurred in the FD group; twenty-seven of the same genes were similarly regulated, along with five additional genes. Fewer expression differences in the DK group were significant compared to normal or the control eyes of the ML and FD groups, but the pattern was similar to that of the ML and FD differential expression patterns. These data suggest that, at the level of the choroid, the gene expression signatures produced by "GO" emmetropization signals are highly similar despite the different visual conditions.

SUBMITTER: He L

PROVIDER: S-EPMC4160062 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Gene expression signatures in tree shrew choroid in response to three myopiagenic conditions.

He Li L Frost Michael R MR Siegwart John T JT Norton Thomas T TT

Vision research 20140727

We examined gene expression in tree shrew choroid in response to three different myopiagenic conditions: minus lens (ML) wear, form deprivation (FD), and continuous darkness (DK). Four groups of tree shrews (n=7 per group) were used. Starting 24 days after normal eye opening (days of visual experience [DVE]), the ML group wore a monocular -5D lens for 2 days. The FD group wore a monocular translucent diffuser for 2 days. The DK group experienced continuous darkness binocularly for 11 days, start ...[more]

PMID: 25072854

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Project description:We compared gene expression signatures in tree shrew sclera produced by three different visual conditions that all produce ocular elongation and myopia: minus-lens wear, form deprivation, and dark treatment.Six groups of tree shrews (n = 7 per group) were used. Starting 24 days after normal eye-opening (days of visual experience [DVE]), two minus-lens groups wore a monocular -5 diopter (D) lens for 2 days (ML-2) or 4 days (ML-4); two form-deprivation groups wore a monocular translucent diffuser for 2 days (FD-2) or 4 days (FD-4). A dark-treatment (DK) group was placed in continuous darkness for 11 days after experiencing a light/dark environment until 17 DVE. A normal colony-reared group was examined at 28 DVE. Quantitative PCR was used to measure the relative differences in mRNA levels for 55 candidate genes in the sclera that were selected, either because they showed differential expression changes in previous ML studies or because a whole-transcriptome analysis suggested they would change during myopia development.The treated eyes in all groups responded with a significant myopic shift, indicating that the myopia was actively progressing. In the ML-2 group, 27 genes were significantly downregulated in the treated eyes, relative to control eyes. In the treated eyes of the FD-2 group, 16 of the same genes also were significantly downregulated and one was upregulated. The two gene expression patterns were significantly correlated (r(2) = 0.90, P < 0.001). After 4 days of treatment, 31 genes were significantly downregulated in the treated eyes of the ML-4 group and three were upregulated. Twenty-nine of the same genes (26 down- and 3 up-regulated) and six additional genes (all downregulated) were significantly affected in the FD-4 group. The response patterns were highly correlated (r(2) = 0.95, P < 0.001). When the DK group (mean of right and left eyes) was compared to the control eyes of the ML-4 group, the direction and magnitude of the gene expression patterns were similar to those of the ML-4 (r(2) = 0.82, P < 0.001, excluding PENK). Similar patterns also were found when the treated eyes of the ML-4, FD-4, and DK groups were compared to the age-matched normal eyes.The very similar gene expression signatures produced in the sclera by the three different myopiagenic visual conditions at different time points suggests that there is a "scleral remodeling signature" in this mammal, closely related to primates. The scleral genes examined did not distinguish between the specific visual stimuli that initiate the signaling cascade that results in axial elongation and myopia.

Project description:Gene expression in tree shrew choroid was examined during the development of minus-lens induced myopia (LIM, a GO condition), after completion of minus-lens compensation (a STAY condition), and early in recovery (REC) from induced myopia (a STOP condition). Five groups of tree shrews (n = 7 per group) were used. Starting 24 days after normal eye-opening (days of visual experience [DVE]), one minus-lens group wore a monocular -5 D lens for 2 days (LIM-2), another minus-lens group achieved stable lens compensation while wearing a monocular -5 D lens for 11 days (LIM-11); a recovery group also wore a -5 D lens for 11 days and then received 2 days of recovery starting at 35 DVE (REC-2). Two age-matched normal groups were examined at 26 DVE and 37 DVE. Quantitative PCR was used to measure the relative differences in mRNA levels in the choroid for 77 candidate genes that were selected based on previous studies or because a whole-transcriptome analysis suggested their expression would change during myopia development or recovery. Small myopic changes were observed in the treated eyes of the LIM-2 group (-1.0 ± 0.2 D; mean ± SEM) indicating eyes were early in the process of developing LIM. The LIM-11 group exhibited complete refractive compensation (-5.1 ± 0.2 D) that was stable for five days. The REC-2 group recovered by 1.3 ± 0.3 D from full refractive compensation. Sixty genes showed significant mRNA expression differences during normal development, LIM, or REC conditions. In LIM-2 choroid (GO), 18 genes were significantly down-regulated in the treated eyes relative to the fellow control eyes and 10 genes were significantly up-regulated. In LIM-11 choroid (STAY), 10 genes were significantly down-regulated and 12 genes were significantly up-regulated. Expression patterns in GO and STAY were similar, but not identical. All genes that showed differential expression in GO and STAY were regulated in the same direction in both conditions. In REC-2 choroid (STOP), 4 genes were significantly down-regulated and 18 genes were significantly up-regulated. Thirteen genes showed bi-directional regulation in GO vs. STOP. The pattern of differential gene expression in STOP was very different from that in GO or in STAY. Significant regulation was observed in genes involved in signaling as well as extracellular matrix turnover. These data support an active role for the choroid in the signaling cascade from retina to sclera. Distinctly different treated eye vs. control eye mRNA signatures are present in the choroid in the GO, STAY, and STOP conditions. The STAY signature, present after full compensation has occurred and the GO visual stimulus is no longer present, may participate in maintaining an elongated globe. The 13 genes with bi-directional expression differences in GO and STOP responded in a sign of defocus-dependent manner. Taken together, these data further suggest that a network of choroidal gene expression changes generate the signal that alters scleral fibroblast gene expression and axial elongation rate.

Project description:Pathological neovascularization in choroid, a leading cause of blindness, is a characteristic of many fundus diseases, such as diabetic retinopathy and age-related macular degeneration. The present study aimed to elucidate the key signaling pathways in choroidal neovascularization (CNV) by analyzing the mRNA profiles of choroid and retina in tree shrews with CNV. We induced choroidal angiogenesis by laser photocoagulation in 15 tree shrews and obtained mRNA profiles of their choroids and retinas by high-throughput transcriptome sequencing. Hierarchical cluster analysis, weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network analysis, hematoxylin and eosin (HE) staining, CD31 immunohistochemistry (IHC), and reverse transcription quantitative PCR (RT-qPCR) were performed. After laser photocoagulation, we obtained a total of 350 differentially expressed genes (DEGs) in the choroid, including 59 genes in Module-FASN ("ME-FASN") module and 28 genes in Module-RPL ("ME-RPL") module. A total of 69 DEGs in retina, including 20 genes in Module-SLC ("ME-SLC") module. Bioinformatics analysis demonstrated that DEGs in choroid were mainly involved in membrane transport; DEGs in "ME-RPL" were prominent in pathways associated with IgA production, antigen presentation, and cell adhesion molecules (CAMs) signaling. DEGs in "ME-FASN" were involved in fatty acid metabolism and PPAR signaling pathway, while DEGs in "ME-SLC" were involved in GABAergic synapse, neuroactive life receptor interaction, cholinergic synapse, and retrograde endocannabinoid signaling pathway. PPI network analysis demonstrated that the ribosomal protein family genes (RPL31, RPL7, RPL26L1, and RPL19) are key factors of "ME-RPL," acyl-CoA superfamily genes (ACACA, ACAT1, ACAA2, and ACACB) and FASN are key factors of "ME-FASN" and superfamily of solid carrier genes (SLC17A6, SLC32A1, SLC12A5, and SLC6A1) and complement genes (C4A, C3, and C2) are key factors of "ME-SLC." In conclusion, the present study discovered the important signal transductions (fatty acid metabolic pathway and CAMs signaling) and genes (ribosomal protein family and the complement system) in tree shrew CNV. We consider that our findings hold implications in unraveling molecular mechanisms that underlie occurrence and development of CNV.

Project description:Tree shrews, one of the closest relatives of primates, have attracted increasing attention as a model of human diseases, particularly for viral infections. As the first line of defense against microbial pathogens, the innate immune system is crucial in tree shrews. Interleukin-6 (IL-6) is important in the pathophysiology of infection, inflammation and cancer, where it promotes disease development or sustains immune reactions. The present study aimed to obtain further insight into the tree shrew IL-6 (tsIL-6) system, and the function of tsIL-6 in the antiviral and antibacterial response. In the present study, the mRNA and genomic sequence of the tsIL-6 gene were characterized, and the tissue distribution and expression profile of this gene were analyzed in response to lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly I:C) treatment. The full-length tsIL-6 mRNA consisted of 1,152 bp with an open reading frame of 627 bp encoding 208 amino acids, a 5'-untranslated region (UTR) of 62 bp, and a 3'-UTR of 436 bp. The genome sequence of the tsIL-6 gene was 5,265 bp in length, comprising of five exons and four introns. The predicted tsIL-6 protein contained a 25-amino-acid-long signal peptide and a conserved IL-6 domain. Phylogenetic analysis based on the coding sequences revealed that tsIL-6 was closely related to IL-6 in humans. Residues crucial for receptor binding were completely conserved in the tree shrew protein. Reverse transcription-polymerase chain reaction analysis revealed that tsIL-6 mRNA was expressed in all examined tissues of healthy tree shrews, with high levels in the muscle and spleen. Following poly I:C challenge, the expression levels of tsIL-6 were upregulated in four tissues associated with immune system, the liver, spleen, kidney and intestine. Taken together, the molecular and bioinformatics analyses based on the IL-6 sequence revealed that the tree shrew has a close phylogenetic association with humans. These results provide insight for future investigations on the structure and function of tsIL-6.

Project description:Hyperopic refractive error is detected by retinal neurons, which generate GO signals through a direct emmetropization signaling cascade: retinal pigment epithelium (RPE) into choroid and then into sclera, thereby increasing axial elongation. To examine signaling early in this cascade, we measured gene expression in the retina and RPE after short exposure to hyperopia produced by minus-lens wear. Gene expression in each tissue was compared with gene expression in combined retina + RPE. Starting 24 days after normal eye opening, three groups of juvenile tree shrews (n = 7 each) wore a monocular -5 D lens. The untreated fellow eye served as a control. The "6h" group wore the lens for 6 h; the "24h" group wore the lens for 24 h; each group provided separate retina and RPE tissues. Group "24hC" wore the lens for 24 h and provided combined retina + RPE tissue. Quantitative PCR was used to measure the relative differences (treated eye vs. control eye) in mRNA levels for 66 candidate genes. In the retina after 6 h, mRNA levels for seven genes were significantly regulated: EGR1 and FOS (early intermediate genes) were down-regulated in the treated eyes. Genes with secreted protein products, BMP2 and CTGF, were down-regulated, whilst FGF10, IL18, and SST were up-regulated. After 24 h the pattern changed; only one of the seven genes still showed differential expression; BMP2 was still down-regulated. Two new genes with secreted protein products, IGF2 and VIP, were up-regulated. In the RPE, consistent with its role in receiving, processing, and transmitting GO signaling, differential expression was found for genes whose protein products are at the cell surface, intracellular, in the nucleus, and are secreted. After 6 h, mRNA levels for 17 genes were down-regulated in the treated eyes, whilst four genes (GJA1, IGF2R, LRP2, and IL18) were up-regulated. After 24 h the pattern was similar; mRNA levels for 14 of the same genes were still down-regulated; only LRP2 remained up-regulated. mRNA levels for six genes no longer showed differential expression, whilst nine genes, not differentially expressed at 6 h, now showed differential expression. In the combined retina + RPE after 24 h, mRNA levels for only seven genes were differentially regulated despite the differential expression of many genes in the RPE. Four genes showed the same expression in combined tissue as in retina alone, including up-regulation of VIP despite significant VIP down-regulation in RPE. Thus, hyperopia-induced GO signaling, as measured by differential gene expression, differs in the retina and the RPE. Retinal gene expression changed between 6 h and 24 h of treatment, suggesting evolution of the retinal response. Gene expression in the RPE was similar at both time points, suggesting sustained signaling. The combined retina + RPE does not accurately represent gene expression in either retina or, especially, RPE. When gene expression signatures were compared with those in choroid and sclera, GO signaling, as encoded by differential gene expression, differs in each compartment of the direct emmetropization signaling cascade.

Dataset Information

Gene expression signatures in tree shrew choroid in response to three myopiagenic conditions.

Publications

Gene expression signatures in tree shrew choroid in response to three myopiagenic conditions.

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