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

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...

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Veröffentlicht in:Nucleic acids research Jg. 45; H. 6; S. 3422 - 3436
Hauptverfasser: Lei, Lei, Yan, Shou-Yu, Yang, Ran, Chen, Jia-Yu, Li, Yumei, Bu, Ye, Chang, Nannan, Zhou, Qinchao, Zhu, Xiaojun, Li, Chuan-Yun, Xiong, Jing-Wei
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Oxford University Press 07.04.2017
Schlagworte:
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
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
ISSN:0305-1048, 1362-4962
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
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content type line 23
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkw1043