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Status |
Public on Mar 31, 2022 |
Title |
RNPS1 inhibits excessive TNF/TNFR signaling to support hematopoiesis in mice |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
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.
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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
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Contributor(s) |
Zhong X, Hildebrand SK |
Citation missing |
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Submission date |
Jul 31, 2020 |
Last update date |
Mar 31, 2022 |
Contact name |
Sara K Hildebrand |
E-mail(s) |
sara.hildebrand@utsouthwestern.edu, shilde9@gmail.com
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Organization name |
UT Southwestern Medical Center
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Department |
Center for the Genetics of Host Defense
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Lab |
Beutler
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Street address |
5323 Harry Hines blvd
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City |
Dallas |
State/province |
TX |
ZIP/Postal code |
75390 |
Country |
USA |
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Platforms (2) |
GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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Samples (21)
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Relations |
BioProject |
PRJNA649939 |
SRA |
SRP274576 |