Prpf31 is essential for the survival and differentiation of retinal progenitor cells by modulating alternative splicing
| Autor: | Yangjun Zhang, Danna Jia, Jamas Reilly, Xiang Chen, Yunqiao Han, Mugen Liu, Xiliang Liu, Pan Gao, Yuwen Huang, Jiayi Tu, Xinhua Shu, Kui Sun, Daji Luo, Yuntong Zhao, Yuexia Lv, Yayun Qin, Jingzhen Li, Fei Liu, Zhaohui Tang, Shanshan Yu |
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| Rok vydání: | 2021 |
| Předmět: |
Retinal degeneration
RNA Splicing Factors PRPF31 DNA Repair Cell Survival AcademicSubjects/SCI00010 DNA repair Neurogenesis Apoptosis Spindle Apparatus Genome Integrity Repair and Replication Retina Gene Knockout Techniques 03 medical and health sciences Exon 0302 clinical medicine Neural Stem Cells Genetics medicine Animals Zebrafish 030304 developmental biology 0303 health sciences biology Alternative splicing Exons Zebrafish Proteins medicine.disease biology.organism_classification Cell biology Alternative Splicing RNA splicing M Phase Cell Cycle Checkpoints CRISPR-Cas Systems Tumor Suppressor Protein p53 030217 neurology & neurosurgery DNA Damage Retinal Neurons |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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