title: Spliceosomal protein eftud2 mutation leads to p53-dependent apoptosis in zebrafish neural progenitors.
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.
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Shou-Yu
authors.initials: SY
authors.lastname: Yan
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Yang
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Jia-Yu
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Bu
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Chang
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Qinchao
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Chuan-Yun
authors.initials: CY
authors.lastname: Li
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Xiong
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000002:abnormalities; D003001:Cloning, Molecular; D005091:Exons; D007438:Introns; D009154:Mutation; D058953:Neural Stem Cells / Q000166:cytology*; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology; D059365:Nonsense Mediated mRNA Decay; D010445:Peptide Elongation Factors / Q000235:genetics*; D012326:RNA Splicing; D000072260:RNA Splicing Factors / Q000235:genetics*; D013116:Spinal Cord / Q000002:abnormalities; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C000621858:Eftud2 protein, zebrafish; D010445:Peptide Elongation Factors; D000072260:RNA Splicing Factors; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C571228:tp53 protein, zebrafish