ZFIN ID: ZDB-PUB-200624-5
Pervasive changes of mRNA splicing in upf1-deficient zebrafish identify rpl10a as a regulator of T cell development
Lawir, D.F., Sikora, K., O'Meara, C.P., Schorpp, M., Boehm, T.
Date: 2020
Source: Proceedings of the National Academy of Sciences of the United States of America   117(27): 15799-15808 (Journal)
Registered Authors: Boehm, Tom, Schorpp, Michael
Keywords: NMD, evolution, ribosomal protein, thymus
Microarrays: GEO:GSE136669
MeSH Terms:
  • Animals
  • Codon, Nonsense/genetics
  • Fertilization/genetics
  • Gene Expression Regulation, Developmental/genetics
  • Glutathione/analogs & derivatives*
  • Glutathione/genetics
  • Homozygote
  • Humans
  • Nonsense Mediated mRNA Decay/genetics*
  • Nonsense Mediated mRNA Decay/immunology
  • RNA Splicing/genetics*
  • RNA, Messenger/genetics
  • RNA-Binding Proteins/genetics*
  • T-Lymphocytes/immunology*
  • Transcription Factors/genetics
  • Transcriptome/genetics
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics*
PubMed: 32571908 Full text @ Proc. Natl. Acad. Sci. USA
The transcriptome of eukaryotic cells is constantly monitored for errors to avoid the production of undesired protein variants. The evolutionarily conserved nonsense-mediated mRNA decay (NMD) pathway degrades aberrant mRNAs, but also functions in the regulation of transcript abundance in response to changed physiological states. Here, we describe a zebrafish mutant of upf1, encoding the central component of the NMD machinery. Fish homozygous for the upf1t20450 allele (Y163X) survive until day 10 after fertilization, presenting with impaired T cell development as one of the most conspicuous features of the mutant phenotype. Analysis of differentially expressed genes identified dysregulation of the pre-mRNA splicing pathway, accompanied by perturbed autoregulation of canonical splicing activators (SRSF) and repressors (HNRNP). In upf1-deficient mutants, NMD-susceptible transcripts of ribosomal proteins that are known for their role as noncanonical splicing regulators were greatly increased, most notably, rpl10a When the levels of NMD-susceptible rpl10a transcripts were artificially increased in zebrafish larvae, T cell development was significantly impaired, suggesting that perturbed autoregulation of rpl10a splicing contributes to failing T cell development in upf1 deficiency. Our results identify an extraribosomal tissue-specific function to rpl10a in the immune system, and thus exemplify the advantages of the zebrafish model to study the effects of upf1-deficiency in the context of a vertebrate organism.