Dataset Information

Transcriptome profiling of the rat retina after optic nerve transection.

ABSTRACT: Glaucoma is a group of eye diseases characterized by alterations in the contour of the optic nerve head (ONH), with corresponding visual field defects and progressive loss of retinal ganglion cells (RGCs). This progressive RGC death is considered to originate in axonal injury caused by compression of the axon bundles in the ONH. However, the molecular pathomechanisms of axonal injury-induced RGC death are not yet well understood. Here, we used RNA sequencing (RNA-seq) to examine transcriptome changes in rat retinas 2 days after optic nerve transection (ONT), and then used computational techniques to predict the resulting alterations in the transcriptional regulatory network. RNA-seq revealed 267 differentially expressed genes after ONT, 218 of which were annotated and 49 unannotated. We also identified differentially expressed transcripts, including potentially novel isoforms. An in silico pathway analysis predicted that CREB1 was the most significant upstream regulator. Thus, this study identified genes and pathways that may be involved in the pathomechanisms of axonal injury. We believe that our data should serve as a valuable resource to understand the molecular processes that define axonal injury-driven RGC death and to discover novel therapeutic targets for glaucoma.

SUBMITTER: Yasuda M

PROVIDER: S-EPMC4926057 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Transcriptome profiling of the rat retina after optic nerve transection.

Yasuda Masayuki M Tanaka Yuji Y Omodaka Kazuko K Nishiguchi Koji M KM Nakamura Orie O Tsuda Satoru S Nakazawa Toru T

Scientific reports 20160629

Glaucoma is a group of eye diseases characterized by alterations in the contour of the optic nerve head (ONH), with corresponding visual field defects and progressive loss of retinal ganglion cells (RGCs). This progressive RGC death is considered to originate in axonal injury caused by compression of the axon bundles in the ONH. However, the molecular pathomechanisms of axonal injury-induced RGC death are not yet well understood. Here, we used RNA sequencing (RNA-seq) to examine transcriptome ch ...[more]

PMID: 27353354

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Project description:PurposeA time-course analysis of gene regulation in the adult rat retina after intraorbital nerve crush (IONC) and intraorbital nerve transection (IONT).MethodsRNA was extracted from adult rat retinas undergoing either IONT or IONC at increasing times post-lesion. Affymetrix RAE230.2 arrays were hybridized and analyzed. Statistically regulated genes were annotated and functionally clustered. Arrays were validated by means of quantative reverse transcription polymerase chain reaction (qRT-PCR) on ten regulated genes at two times post-lesion. Western blotting and immunohistofluorescence for four pro-apoptotic proteins were performed on naïve and injured retinas. Finally, custom signaling maps for IONT- and IONC-induced death response were generated (MetaCore, Genego Inc.).ResultsHere we show that over time, 3,219 sequences were regulated after IONT and 1,996 after IONC. Out of the total of regulated sequences, 1,078 were commonly regulated by both injuries. Interestingly, while IONT mainly triggers a gene upregulation-sustained over time, IONC causes a transitory downregulation. Functional clustering identified the regulation of high interest biologic processes, most importantly cell death wherein apoptosis was the most significant cluster. Ten death-related genes upregulated by both injuries were used for array validation by means of qRT-PCR. In addition, western blotting and immunohistofluorescence of total and active Caspase 3 (Casp3), tumor necrosis factor receptor type 1 associated death domain (TRADD), tumor necrosis factor receptor superfamily member 1a (TNFR1a), and c-fos were performed to confirm their protein regulation and expression pattern in naïve and injured retinas. These analyses demonstrated that for these genes, protein regulation followed transcriptional regulation and that these pro-apoptotic proteins were expressed by retinal ganglion cells (RGCs). MetaCore-based death-signaling maps show that several apoptotic cascades were regulated in the retina following optic nerve injury and highlight the similarities and differences between IONT and IONC in cell death profiling.ConclusionsThis comprehensive time course retinal transcriptome study comparing IONT and IONC lesions provides a unique valuable tool to understand the molecular mechanisms underlying optic nerve injury and to design neuroprotective protocols.

Project description:PurposeTo investigate the optic nerve and macular morphology in patients with optic nerve hypoplasia (ONH) using spectral-domain optical coherence tomography (SD OCT).DesignProspective, cross-sectional, observational study.SubjectsA total of 16 participants with ONH (10 female and 6 male; mean age, 17.2 years; 6 bilateral involvement) and 32 gender-, age-, ethnicity-, and refraction-matched healthy controls.MethodsHigh-resolution SD OCT (Copernicus [Optopol Technology S.A., Zawiercie, Poland], 3 μm resolution) and handheld SD OCT (Bioptigen Inc [Research Triangle Park, NC], 2.6 μm resolution) devices were used to acquire horizontal scans through the center of the optic disc and macula.Main outcome measuresHorizontal optic disc/cup and rim diameters, cup depth, peripapillary retinal nerve fiber layer (RNFL), and thickness of individual retinal layers in participants with ONH and in controls.ResultsPatients with ONH had significantly smaller discs (P < 0.03 and P < 0.001 compared with unaffected eye and healthy controls, respectively), horizontal cup diameter (P < 0.02 for both), and cup depth (P < 0.02 and P < 0.01, respectively). In the macula, significantly thinner RNFL (nasally), ganglion cell layer (GCL) (nasally and temporally), inner plexiform layer (IPL) (nasally), outer nuclear layer (ONL) (nasally), and inner segment (centrally and temporally) were found in patients with ONH compared with the control group (P < 0.05 for all comparisons). Continuation of significantly thicker GCL, IPL, and outer plexiform layer in the central retinal area (i.e., foveal hypoplasia) was found in more than 80% of patients with ONH. Clinically unaffected fellow eyes of patients with ONH showed mild features of underdevelopment. Visual acuity and presence of septo-optic dysplasia were associated with changes in GCL and IPL. Sensitivity and specificity for the detection of ONH based on disc and retinal optical coherence tomography (OCT) parameters were >80%.ConclusionsOur study provides evidence of retinal changes in ONH. In addition to thinning of retina layers mainly involving the RNFL and GCL, signs reminiscent of foveal hypoplasia were observed in patients with ONH. Optic nerve and foveal parameters measured using OCT showed high sensitivity and specificity for detecting ONH, demonstrating their useful for clinical diagnosis.

Dataset Information

Transcriptome profiling of the rat retina after optic nerve transection.

Publications

Transcriptome profiling of the rat retina after optic nerve transection.

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