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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/repair pathways known from studies of immuno-compromised mammals provided an evolutionary cross-validation of the screen design. Unexpectedly, however, certain pre-mRNA processing factor genes, including tnpo3, encoding a regulator of alternative splicing, were also found to play a specific role in early T cell development. In both zebrafish and mouse, TNPO3 deficiency impairs intrathymic T cell differentiation, illustrating evolutionarily conserved and cell type-specific functions of certain pre-mRNA processing factor. Overall design: Taking advantage of the apparent evolutionary conservation of lymphocyte-based immunity, we conducted genetic screens in zebrafish aimed at identifying novel regulators of T lymphocyte development. Apart from mutations in genes encoding lymphoid lineage-specific transcription factors, and components of cytokine signaling and DNA replication/repair pathways, mutations in genes encoding pre-mRNA processing factors were also found. To examine the molecular consequences, transcriptome analyses were conducted for three mutants, snapc3, lsm8, tnpo3.xref:PubMed:27880902ENAzebra fish, lod, T-lymphocyte differentiation, Zebra, leopard danio, DmelCG2684, Danio rerio, Zebra Fish, Danio frankei, Zebrafishes, familial, Fishes, danio, NTef2, Lds, Zebra danios, early, Fs(3)Sz11, genetic, Zebra danio, zebra danio, Horka, B. rerio, Danio rerio frankei, Zebra Fishes, D. rerio, CG2684, T cell development, Fs(3)Horka, T lymphocyte differentiation, Brachydanio rerio, T-cell differentiation., inherited genetic, DmF2, Cyprinus rerio, constitutitional genetic, Fs(3)Hor, hereditary, zebrafish, D. rerios, Brachydanio rerio frankeizebra fish <Danio rerio>, zebra fish, Zebra danio, Zebra, leopard danio, Danio rerio, Zebra Fish, zebra danio, Danio frankei, B. rerio, Zebrafishes, Danio rerio frankei, Zebra Fishes, D. rerio, Brachydanio rerio, Fishes, Cyprinus rerio, danio, Brachydanio rerio frankei., zebrafish, Zebra danios, D. reriosfalseDanio rerioForward genetic screens in zebrafish identify novel molecular pathways regulating early T cell development2025-09-242017-04-19PRJNA310608GSE77480795527880902