PUBLICATION

Spliceosomal protein eftud2 mutation leads to p53-dependent apoptosis in zebrafish neural progenitors

Authors
Lei, L., Yan, S.Y., Yang, R., Chen, J.Y., Li, Y., Bu, Y., Chang, N., Zhou, Q., Zhu, X., Li, C.Y., Xiong, J.W.
ID
ZDB-PUB-161203-16
Date
2017
Source
Nucleic acids research   45(6): 3422-3436 (Journal)
Registered Authors
Xiong, Jing-Wei
Keywords
none
Datasets
GEO:GSE78106
MeSH Terms
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Tumor Suppressor Protein p53/metabolism
  • Neural Stem Cells/cytology*
  • Spinal Cord/abnormalities
  • Mutation
  • Brain/abnormalities
  • Peptide Elongation Factors/genetics*
  • Apoptosis*
  • Exons
  • Animals
  • RNA Splicing Factors/genetics*
  • Cloning, Molecular
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • Neurogenesis/genetics*
  • Transcriptome
  • Introns
  • Neurons/cytology
  • RNA Splicing
  • Nonsense Mediated mRNA Decay
(all 21)
PubMed
27899647 Full text @ Nucleic Acids Res.
Abstract
Haploinsufficiency of EFTUD2 (Elongation Factor Tu GTP Binding Domain Containing 2) is linked to human mandibulofacial dysostosis, Guion-Almeida type (MFDGA), but the underlying cellular and molecular mechanisms remain to be addressed. We report here the isolation, cloning and functional analysis of the mutated eftud2 (snu114) in a novel neuronal mutant fn10a in zebrafish. This mutant displayed abnormal brain development with evident neuronal apoptosis while the development of other organs appeared less affected. Positional cloning revealed a nonsense mutation such that the mutant eftud2 mRNA encoded a truncated Eftud2 protein and was subjected to nonsense-mediated decay. Disruption of eftud2 led to increased apoptosis and mitosis of neural progenitors while it had little effect on differentiated neurons. Further RNA-seq and functional analyses revealed a transcriptome-wide RNA splicing deficiency and a large amount of intron-retaining and exon-skipping transcripts, which resulted in inadequate nonsense-mediated RNA decay and activation of the p53 pathway in fn10a mutants. Therefore, our study has established that eftud2 functions in RNA splicing during neural development and provides a suitable zebrafish model for studying the molecular pathology of the neurological disease MFDGA.
Genes / Markers
Figures
Figure Gallery (8 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
fn10a
    Point Mutation
    1 - 1 of 1
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    Human Disease / Model
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    eftud2MO1-eftud2MRPHLNO
    tp53MO4-tp53MRPHLNO
    upf1MO1-upf1MRPHLNO
    1 - 3 of 3
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    Fish
    Antibodies
    Orthology
    Gene Orthology
    eftud2
    1 - 1 of 1
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    Engineered Foreign Genes
    No data available
    Mapping
    No data available