PUBLICATION

Prpf31 is essential for the survival and differentiation of retinal progenitor cells by modulating alternative splicing

Authors
Li, J., Liu, F., Lv, Y., Sun, K., Zhao, Y., Reilly, J., Zhang, Y., Tu, J., Yu, S., Liu, X., Qin, Y., Huang, Y., Gao, P., Jia, D., Chen, X., Han, Y., Shu, X., Luo, D., Tang, Z., Liu, M.
ID
ZDB-PUB-210123-13
Date
2021
Source
Nucleic acids research   49(4): 2027-2043 (Journal)
Registered Authors
Liu, Mugen
Keywords
none
Datasets
GEO:GSE151273
MeSH Terms
  • CRISPR-Cas Systems
  • Retina/embryology*
  • Cell Survival
  • DNA Repair
  • Neurogenesis/genetics*
  • DNA Damage
  • Gene Knockout Techniques
  • Exons
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Zebrafish Proteins/physiology*
  • Apoptosis
  • Retinal Neurons/cytology
  • Retinal Neurons/metabolism
  • Neural Stem Cells/cytology
  • Neural Stem Cells/metabolism*
  • Tumor Suppressor Protein p53/metabolism
  • Alternative Splicing*
  • Animals
  • Spindle Apparatus/ultrastructure
  • M Phase Cell Cycle Checkpoints
(all 23)
PubMed
33476374 Full text @ Nucleic Acids Res.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (9 images)
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hzu12
    Indel
    ihb135
      Indel
      knu3TgTransgenic Insertion
        nl1TgTransgenic Insertion
          1 - 4 of 4
          Show
          Human Disease / Model
          No data available
          Sequence Targeting Reagents
          Target Reagent Reagent Type
          prpf31CRISPR1-prpf31CRISPR
          1 - 1 of 1
          Show
          Fish
          Antibodies
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          1 - 1 of 1
          Show
          Mapping
          No data available