Abstract
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.
Highlights
Ciliary neurotrophic factor (CNTF) has been tested in clinical trials for human retinal degeneration due to its potent neuroprotective effects in various animal models
We validated our RNA-seq data by comparison with other Retinal degeneration (RD) mouse models and available proteomic data. Results of these molecular analyses demonstrate the impacts of CNTF treatments on the retinal transcriptome in diseased conditions, providing valuable insight for CNTF clinical trials aimed at attenuating retinal degeneration in patients
At postnatal day 25 (P25), when the onset of retinal degeneration had begun in the Rds retina, the mutant retina exhibited significant differences in mRNA expression from wild type littermates for 1322 genes, with 651 genes downregulated and 671 genes upregulated (Fig. 1a)
Summary
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/Prph[2] (P216L) transgenic mouse as a preclinical model for retinitis pigmentosa. 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. We validated our RNA-seq data by comparison with other RD mouse models and available proteomic data Together, results of these molecular analyses demonstrate the impacts of CNTF treatments on the retinal transcriptome in diseased conditions, providing valuable insight for CNTF clinical trials aimed at attenuating retinal degeneration in patients
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