Prpf31 is essential for the survival and differentiation of retinal progenitor cells by modulating alternative splicing
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA635369 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11855600_1.fastq.gz | Fastqsanger.gz | |||
| SRR11855600_2.fastq.gz | Fastqsanger.gz | |||
| SRR11855601_1.fastq.gz | Fastqsanger.gz | |||
| SRR11855601_2.fastq.gz | Fastqsanger.gz | |||
| SRR11855602_1.fastq.gz | Fastqsanger.gz |
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Project description:Dysfunction of splicing factors often result in abnormal cell differentiation and apoptosis, especially in neural tissues. Mutations in pre-mRNAs processing factor 31 (PRPF31) cause autosomal dominant retinitis pigmentosa, a progressive retinal degeneration disease. The transcriptome-wide splicing events specifically regulated by PRPF31 and their biological roles in the development and maintenance of retina are still unclear. Here, we showed that the differentiation and viability of retinal progenitor cells (RPCs) are severely perturbed in prpf31 knockout zebrafish when compared with other tissues at an early embryonic stage. At the cellular level, significant mitotic arrest and DNA damage were observed. These defects could be rescued by the wild-type human PRPF31 rather than the disease-associated mutants. Further bioinformatic analysis and experimental verification uncovered that Prpf31 deletion predominantly causes the skipping of exons with a weak 5′ splicing site. Moreover, genes necessary for DNA repair and mitotic progression are most enriched among the differentially spliced events, which may explain the cellular and tissular defects in prpf31 mutant retinas. This is the first time that Prpf31 is demonstrated to be essential for the survival and differentiation of RPCs during retinal neurogenesis by specifically modulating the alternative splicing of genes involved in DNA repair and mitosis.
2021-01-06 | GSE151273 | GEO
Project description:Mutations in the ubiquitously expressed pre-mRNA processing factor (PRPF) 31, one of the most common cause of dominant form of Retinitis Pigmentosa (RP), lead to retina-specific phenotype. It is uncertain which retinal cell types are affected and animal models do not clearly present the RP phenotype observed in PRPF31 patients. Retinal organoids and retinal pigmented epithelial (RPE) cells derived from human induced pluripotent stem cells (iPSCs) provide potential opportunities for studying human PRPF31-related RP. We demonstrated that RPE cells carrying PRPF31 mutations present important morphological and functional changes and that PRPF31-mutated retinal organoids recapitulate the human RP phenotype, with a rod photoreceptor cell death followed by a loss of cones. The low level of PRPF31 expression may explain the defective phenotypes of PRPF31-mutated RPE and photoreceptor cells, which were not observed in cells derived from asymptomatic patients or after correction of the pathogenic mutation by CRISPR/Cas9. Transcriptome profiles revealed differentially expressed and mis-spliced genes belonging to pathways in line with the observed defective phenotypes. The rescue of RPE and photoreceptor defective phenotypes by PRPF31 gene augmentation, provide the proof of concept for future therapeutic strategies.
2022-08-01 | GSE206529 | GEO
Project description:Mutations in pre-mRNA processing factors (PRPFs) cause autosomal dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed genes cause retinal disease. We have generated transcriptome profiles from RP11 (PRPF31-mutated) patient-derived retinal organoids and retinal pigment epithelium (RPE), as well as Prpf31+/- mouse tissues, which revealed that disrupted alternative splicing occurred for specific splicing programmes. Mis-splicing of genes encoding pre-mRNA splicing proteins was limited to patient-specific retinal cells and Prpf31+/- mouse retinae and RPE. Mis-splicing of genes implicated in ciliogenesis and cellular adhesion was associated with severe RPE defects that include disrupted apical-basal polarity, reduced trans-epithelial resistance and phagocytic capacity, and decreased cilia length and incidence. Disrupted cilia morphology also occurred in patient-derived photoreceptors, associated with progressive degeneration and cellular stress. In situ gene-editing of a pathogenic mutation rescued protein expression and key cellular phenotypes in RPE and photoreceptors, providing proof-of-concept for future therapeutic strategies.
2018-08-20 | PXD010821 | Pride
Project description:Dysfunction of splicing factors often result in abnormal cell differentiation and apoptosis, especially in neural tissues. Mutations in pre-mRNAs processing factor 31 (PRPF31) cause autosomal dominant retinitis pigmentosa, a progressive retinal degeneration disease. The transcriptome-wide splicing events specifically regulated by PRPF31 and their biological roles in the development and maintenance of retina are still unclear. Here, we showed that the differentiation and viability of retinal progenitor cells (RPCs) are severely perturbed in prpf31 knockout zebrafish when compared with other tissues at an early embryonic stage. At the cellular level, significant mitotic arrest and DNA damage were observed. These defects could be rescued by the wild-type human PRPF31 rather than the disease-associated mutants. Further bioinformatic analysis and experimental verification uncovered that Prpf31 deletion predominantly causes the skipping of exons with a weak 5' splicing site. Moreover, genes necessary for DNA repair and mitotic progression are most enriched among the differentially spliced events, which may explain the cellular and tissular defects in prpf31 mutant retinas. This is the first time that Prpf31 is demonstrated to be essential for the survival and differentiation of RPCs during retinal neurogenesis by specifically modulating the alternative splicing of genes involved in DNA repair and mitosis.
| S-EPMC7913766 | biostudies-literature
Project description:Epigenetic adaptation prolongs photoreceptor survival during retinal degeneration
| PRJNA563908 | ENA
Project description:Pre-mRNA splicing is a precise regulated process, and is crucial for system development and homeostasis maintenance. Mutations in spliceosomal components have been found in various hematopoietic malignancies (HMs), and have been considered as oncogenic derivers of HMs. However, the role of spliceosomal components in normal and malignant hematopoiesis remain largely unknown. Pre-mRNA processing factor 31 (PRPF31) is a constitutive spliceosomal component, which mutations are associated with autosomal dominant retinitis pigmentosa. PRPF31 was found to be mutated in several HMs, but the function of PRPF31 in normal hematopoiesis has not been explored. In this study, we generated a prpf31 knockout zebrafish line, and discovered that prpf31 mutants exhibited severe defects in hematopoietic stem and progenitor cell (HSPC) expansion and its sequentially differentiated lineages. Immunofluorescence results showed that Prpf31 deficient HSPCs underwent malformed mitosis and M phase arrest during HSPC expansion. Transcriptome analysis and experimental validations revealed that Prpf31 deficiency extensively perturbed the alternative splicing of mitosis-related genes. Collectively, our findings elucidate a previously undescribed role for Prpf31 in HSPC expansion, through regulating the alternative splicing of mitosis-related genes.
2022-04-07 | GSE171661 | GEO
Project description:Retinal microvascularization can provide important informations to systemic vascular phenomena. The non-invasive quantitative description of the retinal vascularization is now possible by performing OCT-angiography and their image analysis software (vascular density and retinal perfusion). Systemic microvacular changes during the establishment of oncological treatment by targeted antiangiogenic therapy are little described in the literature. The objective of this pilot study is to describe the evolution of the retinal vascular density of patients with antiangiogenic drugs. In addition, the evolution of the retinal vascular density of patients on antiangiogenic drugs will study as a function of the response to the treatment and the toxicity of these treatments.
| 2382594 | ecrin-mdr-crc
Project description:The development of the central nervous system (CNS) is a complex process that must be exquisitely controlled at multiple levels to ensure the production of appropriate types and quantity of neurons. RNA alternative polyadenylation (APA) contributes to transcriptome diversity and gene regulation and has recently been shown to be widespread in the CNS. However, previous studies have been primarily focused on the tissue specificity of APA and developmental APA change of whole model organisms, a systematic survey of APA usage is lacking during CNS development. Here we conducted global analysis of APA during mouse retinal development, and identified stage-specific polyadenylation (pA) sites that are enriched for genes critical for retinal development and visual perception. Moreover, we demonstrated 3’UTR lengthening and increased usage of intronic pA sites over development that would result in gaining many different RBP (RNA binding protein) and miRNA target sites. Furthermore, we showed that a considerable number of polyadenylated lncRNAs are co-expressed with protein-coding genes involved in retinal development and functions. Together, our data indicate that APA is highly and dynamically regulated during retinal development and maturation, suggesting that APA may serve as a crucial mechanism of gene regulation underlying the delicate process of CNS development.
2017-04-09 | GSE80206 | GEO
Project description:By removing MLL1 from mouse retinal progenitors, we discovered that MLL1 plays multiplex roles in retinal development by regulating: 1) progenitor cell proliferation and cell cycle progression; 2) retinal cell composition; 3) maintenance of horizontal neurons; 4) formation of functional synapses between neuronal layers; and 5) visual function development. Altogether, our results suggest that MLL1 is an indispensable regulator for the development of retinal structure and function.
2018-08-15 | GSE103264 | GEO
Project description:The type of cell fate decisions a progenitor can make in the developing nervous system are dependent on a combination of cell intrinsic gene expression programs and cell extrinsic signaling molecules that influence expression programs. Moreover, both the progenitor’s spatial location in the tissue and time at which it exists during development can, to varying degrees, influence the competency of differentiation. Here, we use the developing mouse retina to understand how signaling factors in the retinal niche can influence a progenitor to become unipotentially restricted to differentiate into cone photoreceptors, and how this competency changes over the course of retinal development. We show that the secreted inhibitory protein COCO causes progenitors to become cone restricted, and that the competency for this restricted differentiation is maintained throughout retinal development. Using RNA-sequencing, we identify the transcription factor Sox15 as a potential novel marker of restricted progenitors in the developing retina, and that it acts in response to COCO’s effects. Knockdown experiments indicate that this novel retinal transcription factor is involved in the survival of retinal progenitors and promotes cone differentiation by inhibiting differentiation into alternative photoreceptor types.
2024-12-10 | GSE283880 | GEO