Zebrafish rbm8a and magoh mutants reveal EJC developmental functions and new 3′UTR intron-containing NMD targets

Autoři: Pooja Gangras aff001;  Thomas L. Gallagher aff001;  Michael A. Parthun aff001;  Zhongxia Yi aff001;  Robert D. Patton aff002;  Kiel T. Tietz aff001;  Natalie C. Deans aff001;  Ralf Bundschuh aff002;  Sharon L. Amacher aff001;  Guramrit Singh aff001
Působiště autorů: Department of Molecular Genetics, The Ohio State University, Ohio, United States of America aff001;  Center for RNA Biology, The Ohio State University, Ohio, United States of America aff002;  Department of Physics, The Ohio State University, Ohio, United States of America aff003;  Department of Chemistry and Biochemistry, The Ohio State University, Ohio, United States of America aff004;  Division of Hematology, Department of Internal Medicine, The Ohio State University, Ohio, United States of America aff005;  Department of Biological Chemistry and Pharmacology, The Ohio State University, Ohio, United States of America aff006;  Center for Muscle Health and Neuromuscular Disorders, The Ohio State University and Nationwide Children’s Hospital, Ohio, United States of America aff007
Vyšlo v časopise: Zebrafish rbm8a and magoh mutants reveal EJC developmental functions and new 3′UTR intron-containing NMD targets. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008830
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008830


Many post-transcriptional mechanisms operate via mRNA 3′UTRs to regulate protein expression, and such controls are crucial for development. We show that homozygous mutations in two zebrafish exon junction complex (EJC) core genes rbm8a and magoh leads to muscle disorganization, neural cell death, and motor neuron outgrowth defects, as well as dysregulation of mRNAs subjected to nonsense-mediated mRNA decay (NMD) due to translation termination ≥ 50 nts upstream of the last exon-exon junction. Intriguingly, we find that EJC-dependent NMD also regulates a subset of transcripts that contain 3′UTR introns (3′UI) < 50 nts downstream of a stop codon. Some transcripts containing such stop codon-proximal 3′UI are also NMD-sensitive in cultured human cells and mouse embryonic stem cells. We identify 167 genes that contain a conserved proximal 3′UI in zebrafish, mouse and humans. foxo3b is one such proximal 3′UI-containing gene that is upregulated in zebrafish EJC mutant embryos, at both mRNA and protein levels, and loss of foxo3b function in EJC mutant embryos significantly rescues motor axon growth defects. These data are consistent with EJC-dependent NMD regulating foxo3b mRNA to control protein expression during zebrafish development. Our work shows that the EJC is critical for normal zebrafish development and suggests that proximal 3′UIs may serve gene regulatory function in vertebrates.

Klíčová slova:

Axons – Embryos – Gene expression – Gene regulation – Introns – Messenger RNA – Motor neurons – Zebrafish


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