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
  • Animals
  • Apoptosis*
  • Brain/abnormalities
  • Cloning, Molecular
  • Exons
  • Introns
  • Mutation
  • Neural Stem Cells/cytology*
  • Neurogenesis/genetics*
  • Neurons/cytology
  • Nonsense Mediated mRNA Decay
  • Peptide Elongation Factors/genetics*
  • RNA Splicing
  • RNA Splicing Factors/genetics*
  • Spinal Cord/abnormalities
  • Transcriptome
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
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
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping