PUBLICATION

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

Authors

Gangras, P., Gallagher, T.L., Parthun, M.A., Yi, Z., Patton, R.D., Tietz, K.T., Deans, N.C., Bundschuh, R., Amacher, S.L., Singh, G.

ID

ZDB-PUB-200606-31

Date

2020

Source

PLoS Genetics 16: e1008830 (Journal)

Registered Authors

Amacher, Sharon, Gallagher, Thomas, Tietz, Kiel

Keywords

none

MeSH Terms

Embryo, Nonmammalian
Mice
Animals, Genetically Modified
Zebrafish Proteins/metabolism*
Up-Regulation
Datasets as Topic
Neurogenesis/genetics*
Introns/genetics
RNA-Seq
Gene Expression Regulation, Developmental*
Zebrafish/genetics
Zebrafish/growth & development
Humans
3' Untranslated Regions/genetics
Nonsense Mediated mRNA Decay/genetics*
Neuronal Outgrowth/genetics
Sequence Alignment
Mutagenesis
Exons/genetics
Muscle, Skeletal/innervation
Forkhead Transcription Factors/metabolism*
Homozygote
Axons/physiology
RNA-Binding Proteins/genetics
RNA-Binding Proteins/metabolism*
Peptide Chain Termination, Translational
Animals
Nuclear Proteins/genetics
RNA, Messenger/metabolism
Codon, Terminator
Mutation
Gene Regulatory Networks/genetics

(all 32)

PubMed

32502192 Full text @ PLoS Genet.

Abstract

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.

Genes / Markers

Figures