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

English version

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: https://doi.org/10.1371/journal.pgen.1008830

Souhrn

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

Zdroje

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Článek Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology

Článek Identification of Clec4b as a novel regulator of bystander activation of auto-reactive T cells and autoimmune disease

Článek Genetic analysis of osteoblast activity identifies Zbtb40 as a regulator of osteoblast activity and bone mass

Článek In vivo modeling of metastatic human high-grade serous ovarian cancer in mice

Článek GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation

Článek An Africa-wide genomic evolution of insecticide resistance in the malaria vector Anopheles funestus involves selective sweeps, copy number variations, gene conversion and transposons

Článek BK channel density is regulated by endoplasmic reticulum associated degradation and influenced by the SKN-1A/NRF1 transcription factor

Článek Adaptation of codon usage to tRNA I34 modification controls translation kinetics and proteome landscape

Článek Nitric oxide mediates neuro-glial interaction that shapes Drosophila circadian behavior