Pervasive changes of mRNA splicing in -deficient zebrafish identify as a regulator of T cell development.

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 , encoding the central component of the NMD machinery. Fish homozygous for the 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 -deficient mutants, NMD-susceptible transcripts of ribosomal proteins that are known for their role as noncanonical splicing regulators were greatly increased, most notably, When the levels of NMD-susceptible transcripts were artificially increased in zebrafish larvae, T cell development was significantly impaired, suggesting that perturbed autoregulation of splicing contributes to failing T cell development in deficiency. Our results identify an extraribosomal tissue-specific function to in the immune system, and thus exemplify the advantages of the zebrafish model to study the effects of -deficiency in the context of a vertebrate organism.