Impacts of ciliary neurotrophic factor on the retinal transcriptome in a mouse model of photoreceptor degeneration
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ABSTRACT:
PROVIDER: PRJNA892591 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR21986261_1.fastq.gz | Fastqsanger.gz | |||
| SRR21986261_2.fastq.gz | Fastqsanger.gz | |||
| SRR21986262_1.fastq.gz | Fastqsanger.gz | |||
| SRR21986262_2.fastq.gz | Fastqsanger.gz | |||
| SRR21986263_1.fastq.gz | Fastqsanger.gz |
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Project description:Ciliary neurotrophic factor (CNTF) has been tested in clinical trials for human retinal degeneration due to its potent neuroprotective effects in various animal models. To decipher CNTF-triggered molecular events in the degenerating retina, high-throughput RNA sequencing analyses were performed using the Rds/Prph2 (P216L) transgenic mouse as a preclinical model for retinitis pigmentosa. Retinal transcriptome data was obtained for untreated wild type retinas, Rds retinas treated with a lentivirus expressing CNTF from postnatal day 25 to 35, and Rds retinas similarly treated with a control lentivirus expressing GFP. Comparisons of transcriptome data detect significant changes between wild type and Rds retinas. In addition, RNA-seq data reveal elevation of transcripts in the innate immune system and growth factor signaling, as well as altered neuronal transmission and metabolism in CNTF-treated Rds retinas. These results demonstrate the influence of exogenous CNTF on the retinal transcriptome landscape and illuminate likely CNTF impacts in degenerating human retinas.
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Project description:Ciliary neurotrophic factor (CNTF) has been tested in clinical trials for human retinal degeneration due to its potent neuroprotective effects in various animal models. To decipher CNTF-triggered molecular events in the degenerating retina, we performed high-throughput RNA sequencing analyses using the Rds/Prph2 (P216L) transgenic mouse as a preclinical model for retinitis pigmentosa. In the absence of CNTF treatment, transcriptome alterations were detected at the onset of rod degeneration compared with wild type mice, including reduction of key photoreceptor transcription factors Crx, Nrl, and rod phototransduction genes. Short-term CNTF treatments caused further declines of photoreceptor transcription factors accompanied by marked decreases of both rod- and cone-specific gene expression. In addition, CNTF triggered acute elevation of transcripts in the innate immune system and growth factor signaling. These immune responses were sustained after long-term CNTF exposures that also affected neuronal transmission and metabolism. Comparisons of transcriptomes also uncovered common pathways shared with other retinal degeneration models. Cross referencing bulk RNA-seq with single-cell RNA-seq data revealed the CNTF responsive cell types, including Müller glia, rod and cone photoreceptors, and bipolar cells. Together, these results demonstrate the influence of exogenous CNTF on the retinal transcriptome landscape and illuminate likely CNTF impacts in degenerating human retinas.
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Project description:The photoreceptor outer segment is the canonical example of a modified and highly specialised cilium, with an expanded membrane surface area in the form of discs or lamellae for efficient light detection. Many ciliary proteins are essential for normal photoreceptor function and cilium dysfunction often results in retinal degeneration leading to impaired vision. Herein, we investigate the function and localisation of the ciliary G-protein RAB28 in zebrafish cone photoreceptors. CRISPR-Cas9 generated rab28 mutant zebrafish display a reduction in shed outer segment material in the RPE at 1 month post fertilisation (mpf), but otherwise normal retinal structure and visual function up to 12 mpf. Cone photoreceptorspecific transgenic reporter lines show Rab28 localises almost exclusively to outer segments, independently of nucleotide binding. Co-immunoprecipitation analysis demonstrates tagged Rab28 interacts with components of the phototransduction cascade, including opsins, Phosphodiesterase 6C and Guanylate Cyclase 2D. Our data shed light on RAB28 function in cones and provide a model for RAB28-associated cone-rod dystrophy
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Project description:To investigate pathogenic mechanisms in such instances, we have characterized rod photoreceptor and retinal gene expression changes in response to a defined insult to photoreceptor structure, using the retinal degeneration slow (rds) mouse model. Global gene expression profiling was performed on flow-sorted rds and wild-type rod photoreceptors immediately prior and subsequent to times at which OSs are normally elaborated. Dysregulated genes were identified via microarray hybridization, and selected candidates were validated using quantitative PCR analyses. We identified a single key gene, Egr1, that was dysregulated in a sustained fashion in rds rod photoreceptors and in the retina. Egr1 upregulation was associated with microglial activation and migration, into the outer retina at times subsequent to the major peak of photoreceptor cell death. Interestingly, this response was accompanied by neurotrophic factor upregulation. We hypothesize that activation of Egr1 and neurotrophic factors represents a protective immune mechanism, contributing to the characteristically slow retinal degeneration of the rds mouse model. We had two conditions WT and Rds-KO at 4 different time points: postnatal (P) 6, P9, P14 and P21.
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