NMD is essential for hematopoietic stem and progenitor cells and for eliminating by-products of programmed DNA rearrangements
Author
Summary, in English
Nonsense-mediated mRNA decay (NMD) is a post-transcriptional surveillance process that eliminates mRNAs containing premature termination codons (PTCs). NMD has been hypothesized to impact on several aspects of cellular function; however, its importance in the context of a mammalian organism has not been addressed in detail. Here we use mouse genetics to demonstrate that hematopoietic-specific deletion of Upf2, a core NMD factor, led to the rapid, complete, and lasting cell-autonomous extinction of all hematopoietic stem and progenitor populations. In contrast, more differentiated cells were only mildly affected in Upf2-null mice, suggesting that NMD is mainly essential for proliferating cells. Furthermore, we show that UPF2 loss resulted in the accumulation of nonproductive rearrangement by-products from the Tcrb locus and that this, as opposed to the general loss of NMD, was particularly detrimental to developing T-cells. At the molecular level, gene expression analysis showed that Upf2 deletion led to a profound skewing toward up-regulated mRNAs, highly enriched in transcripts derived from processed pseudogenes, and that NMD impacts on regulated alternative splicing events. Collectively, our data demonstrate a unique requirement of NMD for organismal survival.
Department/s
- Immunology
- Stem Cell Center
Publishing year
2008
Language
English
Pages
1381-1396
Publication/Series
Genes & Development
Volume
22
Issue
10
Document type
Journal article
Publisher
Cold Spring Harbor Laboratory Press (CSHL)
Topic
- Genetics
Keywords
- alternative splicing
- programmed DNA rearrangements
- T-cell development
- nonsense-mediated mRNA decay
- hematopoietic stem and progenitor cells
- pseudogenes
Status
Published
Research group
- Immunology
ISBN/ISSN/Other
- ISSN: 1549-5477