PUBLICATION
Pervasive changes of mRNA splicing in upf1-deficient zebrafish identify rpl10a as a regulator of T cell development
- Authors
- Lawir, D.F., Sikora, K., O'Meara, C.P., Schorpp, M., Boehm, T.
- ID
- ZDB-PUB-200624-5
- 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
- Datasets
- 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
Citation
Lawir, D.F., Sikora, K., O'Meara, C.P., Schorpp, M., Boehm, T. (2020) Pervasive changes of mRNA splicing in upf1-deficient zebrafish identify rpl10a as a regulator of T cell development. Proceedings of the National Academy of Sciences of the United States of America. 117(27):15799-15808.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping