Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration
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ABSTRACT:
PROVIDER: PRJNA576715 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10254951_1.fastq.gz | Fastqsanger.gz | |||
| SRR10254951_2.fastq.gz | Fastqsanger.gz | |||
| SRR10254952_1.fastq.gz | Fastqsanger.gz | |||
| SRR10254952_2.fastq.gz | Fastqsanger.gz | |||
| SRR10254953_1.fastq.gz | Fastqsanger.gz |
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Project description:Rab and associated effector proteins are involved in all steps of cargo transport through subcellular compartments during the endocytic pathway that participates in multiple cellular processes including signal transduction, protein recycling and degradation. We identified Rabgef1 (also called Rabex-5) as the only differentially expressed Rab-associated gene that exhibits strong concordance with photoreceptor maturation by mining the retinal transcriptome data. The retinas of Rabgef1-/- mice exhibit defects in photoreceptor morphology, followed by cell death, and almost complete loss of both rod and cone photoreceptor function within 3 weeks after birth. Like other cells/tissues, Rabgef1 interacts with Rabaptin5 in the retina and its loss leads to reduced early endosomes in the photoreceptor inner segments as indicated by EEA1 immunostaining. Rabgef1-/- photoreceptors abnormally accumulate autophagosomes, and proteomic profiling of endosome-enriched fractions demonstrate significant depletion of phototransduction and mitochondrial proteins. Transcriptome analysis of developing retina before the degeneration is evident reveals energy metabolism modules and gene regulatory landscape that likely suggest the trajectory of cellular changes leading to photoreceptor degeneration. Our results directly implicate endocytic pathway in outer segment biogenesis and photoreceptor development and provide strong evidence that endocytosis defects in the retina can trigger upregulation of autophagic mechanisms. We also suggest that Rabgef1 and components of the endocytic and autophagic pathways should be considered as candidates for human retinopathies.
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Project description:Retinitis pigmentosa is an inherited disease with sequential retinal degeneration of rod then cone photoreceptors leading to blindness. As in this human syndrome the rd1 mouse model carries a recessive mutation in the rod-specific cGMP phosphodiesterase beta subunit gene leading to rod followed by cone photoreceptor death. The cascade of early events leading to the induction of rod cell death through apoptosis remains unknown. We report a differential whole-genome expression profiling analysis of the wild-type and rd1 mouse retinal transcriptional program using high-density oligonucleotide microarrays with a time series experiment spanning the entire rod photoreceptor degeneration process. Among the 1252 genes found to be significantly differentially expressed, a key group of 19 loci showed distinct differences in expression early in development, suggesting that these genes of clinical interest may play a fundamental role in the induction of the rod photoreceptor degeneration.
2020-09-25 | GSE62020 | GEO
Project description:Rab-GTPases and associated effectors mediate cargo transport through the endomembrane system of eukaryotic cells, regulating key processes such as membrane turnover, signal transduction, protein recycling and degradation. Using developmental transcriptome data, we identified Rabgef1 (encoding the protein RabGEF1 or Rabex-5) as the only gene associated with Rab GTPases that exhibited strong concordance with retinal photoreceptor differentiation. Loss of Rabgef1 in mice (Rabgef1-/-) resulted in defects specifically of photoreceptor morphology and almost complete loss of both rod and cone function as early as eye opening; however, aberrant outer segment formation could only partly account for visual function deficits. RabGEF1 protein in retinal photoreceptors interacts with Rabaptin-5, and RabGEF1 absence leads to reduction of early endosomes consistent with studies in other mammalian cells and tissues. Electron microscopy analyses reveal abnormal accumulation of macromolecular aggregates in autophagosome-like vacuoles and enhanced immunostaining for LC3A/B and p62 in Rabgef1-/- photoreceptors, consistent with compromised autophagy. Transcriptome analysis of the developing Rabgef1-/- retina reveals altered expression of 2469 genes related to multiple pathways including phototransduction, mitochondria, oxidative stress and endocytosis, suggesting an early trajectory of photoreceptor cell death. Our results implicate an essential role of the RabGEF1-modulated endocytic and autophagic pathways in photoreceptor differentiation and homeostasis. We propose that RabGEF1 and associated components are potential candidates for syndromic traits that include a retinopathy phenotype.
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Project description:Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss in many retinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor NRL. The loss of Nrl in mice (Nrl-/-) results in a retina with predominantly S-opsin containing cones that exhibit molecular and functional characteristics of WT cones. Here we report that Nrl-/- retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by four months of age, resulting in a thinned but intact outer nuclear layer with residual cones expressing S- and M-opsins and a preserved photopic ERG. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of stress response and inflammation genes, implying their involvement in cone death. The Nrl-/- retina illustrates the long-term viability of cones in the absence of rods and may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone-dominant human macula. Targets were generated from a pair of retinas (one Nrl-/- mouse) per biological replicate. Four biological replicates were generated for each of the five aging timepoints (1, 2, 4, 6, and 10 months post natal).
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Project description:Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss in many retinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor NRL. The loss of Nrl in mice (Nrl-/-) results in a retina with predominantly S-opsin containing cones that exhibit molecular and functional characteristics of WT cones. Here we report that Nrl-/- retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by four months of age, resulting in a thinned but intact outer nuclear layer with residual cones expressing S- and M-opsins and a preserved photopic ERG. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of stress response and inflammation genes, implying their involvement in cone death. The Nrl-/- retina illustrates the long-term viability of cones in the absence of rods and may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone-dominant human macula.
2011-11-15 | GSE33674 | GEO
Project description:Aging is associated with a decline in visual function and increased prevalence of ocular disease, correlating with changes in the transcriptome and epigenome of cells in the eye. Here, we sought to test if age-associated changes in gene expression patterns in the eye directly contribute to the increased risk of retinal degeneration. To do this, we performed a targeted photoreceptor specific RNAi screen in Drosophila to identify gene regulatory factors that result in premature, age-dependent retinal degeneration. From an initial set of 155 RNAi lines each targeting a unique gene and spanning a diverse set of gene regulatory factors, we identified 18 high confidence target genes whose decreased expression in adult photoreceptors leads to premature and progressive retinal degeneration. The 18 target genes were enriched for factors involved in the regulation of transcription initiation, pausing, and elongation, suggesting that these processes are essential for maintaining the health of aging photoreceptors. To identify the genes regulated by these factors, we profiled the photoreceptor transcriptome in a subset of lines. Strikingly, two of the 18 target genes, Spt5 and domino, show substantially similar changes in gene expression to those observed with advanced age. Together, our data suggests that dysregulation of the mechanisms involved in transcription initiation and elongation plays a key role in shaping the transcriptome of aging photoreceptors. Further, our findings indicate that the age-dependent changes in gene expression not only correlate, but might also contribute to increased risk of retinal degeneration.
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Project description:Inherited retinal diseases and aged related macular degeneration are main causes of blindness that involves irreversible photoreceptor loss. Gene therapy approaches do not prevent photoreceptor degeneration during disease progression, and to date protocols for generating photoreceptors from pluripotent stem cells do not exist. Therefore, transplantation of photoreceptors containing retinal organoids is considered a potential option. However, in vitro formation of organoids requires animal-derived materials and they vary considerably in cell composition between batches, which strongly limits their applications in therapy. Here, we show that human recombinant retina-specific laminin isoform LN523, normally present in the extra cellular matrix ECM surrounding photoreceptors, supports differentiation of pluripotent embryonic stem cells to photoreceptor progenitors in vitro. Using a rabbit macular degeneration model, the transplanted and engrafted cells mature in vivo and form synaptic connectivity with the host retina. Furthermore, addition of a rod-derived cone viability factor increased the formation of cone photoreceptors. These results may pave the way for cell therapy treatment of macular degeneration.
2023-03-26 | GSE161414 | GEO
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2023-03-26 | GSE161416 | GEO
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2022-02-01 | GSE183117 | GEO