Forward genetic screens in zebrafish identify pre-mRNA-processing pathways regulating early T cell development

Abstract

ymphocytes represent basic components of verte brate adaptive immune systems, suggesting the util ity 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 re vealed several major genetic pathways. The iden tification of lineage-specific transcription factors and specific components of cytokine signaling and DNA replication and/or repair pathways known from studies of immunocompromised mammals pro vided an evolutionary cross-validation of the screen design. Unexpectedly, however, genes encoding proteins required for pre-mRNA processing were en riched in the collection of mutants identified here. In both zebrafish and mice, deficiency of the splice regulator TNPO3 impairs intrathymic T cell differenti ation, illustrating the evolutionarily conserved and cell-type-specific functions of certain pre-mRNA processing factors for T cell development.