NMD is essential for hematopoietic stem and progenitor cells and for eliminating by-products of programmed DNA rearrangements.

Journal article

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.

Authors: Weischenfeldt, J; Damgaard, I; Bryder, D; Theilgaard-Mönch, K; Thoren, L

• Journal: Genes and development
• Volume: 22
• Issue: 10
• Pages: 1381-1396
• Publication date: 2008-05-01
• DOI: 10.1101/gad.468808
• EISSN: 1549-5477
• ISSN: 0890-9369
• Language: English
• Keywords: Models, Biological; RNA Stability; Carrier Proteins; Oligonucleotide Array Sequence Analysis; Sequence Deletion; Cells, Cultured; Hematopoietic Stem Cells; Gene Rearrangement; Base Sequence; Codon, Nonsense; Animals; Mice, Transgenic; Humans; Gene Expression Profiling; Mice; Mice, Inbred C57BL; Lymphoid Progenitor Cells