ZFIN ID: ZDB-PUB-161203-16
Spliceosomal protein eftud2 mutation leads to p53-dependent apoptosis in zebrafish neural progenitors
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.
Date: 2017
Source: Nucleic acids research   45(6): 3422-3436 (Journal)
Registered Authors: Xiong, Jing-Wei
Keywords: none
Microarrays: 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.
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.