TY - JOUR

T1 - NMD is essential for hematopoietic stem and progenitor cells and for eliminating by-products of programmed DNA rearrangements.

AU - Weischelfeldt, Joachim Lütken

AU - Damgaard, Inge

AU - Bryder, David

AU - Theilgaard-Mönch, Kim

AU - Thoren, Lina A

AU - Nielsen, Finn Cilius

AU - Jacobsen, Sten Eirik W

AU - Nerlov, Claus

AU - Porse, Bo Torben

N1 - Keywords: Animals; Base Sequence; Carrier Proteins; Cells, Cultured; Codon, Nonsense; Gene Expression Profiling; Gene Rearrangement; Hematopoietic Stem Cells; Humans; Lymphoid Progenitor Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Oligonucleotide Array Sequence Analysis; RNA Stability; Sequence Deletion

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1101/gad.468808

DO - 10.1101/gad.468808

M3 - Journal article

C2 - 18483223

VL - 22

SP - 1381

EP - 1396

JO - Genes & Development

JF - Genes & Development

SN - 0890-9369

IS - 10

ER -