RNPS1 inhibits excessive TNF/TNFR signaling to support hematopoiesis in mice

Null mutations of spliceosome components or cofactors are homozygous lethal in eukaryotes, but viable hypomorphic mutations provide an opportunity to understand the physiological impact of individual splicing proteins. We describe a viable missense allele of Rnps1, encoding an essential regulator of splicing and nonsense-mediated decay, identified in a mouse genetic screen for altered immune cell development. Homozygous mice displayed a stem cell-intrinsic defect in hematopoiesis of all lineages due to excessive apoptosis induced by TNF-dependent death signaling. Numerous splicing variants were observed in Rnps1 mutant splenic CD8+ T and HSC cells, potentially driven by dysregulated splicing, characterized by magnification of both intron retention and exon skipping. Strikingly, Tnf knockout rescued all hematopoietic cells to normal or near-normal levels in Rnps1 mutant mice. Thus, RNPS1 is necessary for accurate splicing, without which disinhibited TNF signaling triggers hematopoietic cell death. Overall design: Examination of transcript abundance and splicing variants in Rnps1+/+;Tnf+/+, Rnps1+/+;Tnf-/-, Rnps1F181I/F181I;Tnf+/+, or Rnps1F181I/F181I;Tnf-/- splenic CD8+ T and HSC cells