Forward Genetic Screens in Zebrafish Identify Pre-mRNA-Processing Pathways Regulating Early T Cell Development

Cell Rep. 2016 Nov 22;17(9):2259-2270. doi: 10.1016/j.celrep.2016.11.003.


Lymphocytes represent basic components of vertebrate adaptive immune systems, suggesting the utility of non-mammalian models to define the molecular basis of their development and differentiation. Our forward genetic screens in zebrafish for recessive mutations affecting early T cell development revealed several major genetic pathways. The identification of lineage-specific transcription factors and specific components of cytokine signaling and DNA replication and/or repair pathways known from studies of immunocompromised mammals provided an evolutionary cross-validation of the screen design. Unexpectedly, however, genes encoding proteins required for pre-mRNA processing were enriched in the collection of mutants identified here. In both zebrafish and mice, deficiency of the splice regulator TNPO3 impairs intrathymic T cell differentiation, illustrating the evolutionarily conserved and cell-type-specific functions of certain pre-mRNA-processing factors for T cell development.

Keywords: T cell development; genetic screen; immunodeficiency; mouse; pre-mRNA splicing; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Epistasis, Genetic
  • Gene Expression Regulation, Developmental
  • Genetic Testing*
  • Larva / genetics
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation / genetics
  • Organ Specificity / genetics
  • RNA Precursors / genetics*
  • RNA Precursors / metabolism
  • RNA Processing, Post-Transcriptional / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ribonucleoproteins, Small Nuclear / metabolism
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / metabolism*
  • Transcriptome / genetics
  • Zebrafish / genetics*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism
  • beta Karyopherins / deficiency
  • beta Karyopherins / metabolism


  • RNA Precursors
  • RNA, Messenger
  • Ribonucleoproteins, Small Nuclear
  • Zebrafish Proteins
  • beta Karyopherins