QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Research Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Weischenfeldt, J. Articles by Porse, B. T. PubMed PubMed Citation Articles by Weischenfeldt, J. Articles by Porse, B. T. Social Bookmarking                   What's this?

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

¹ Section for Gene Therapy Research, Copenhagen University Hospital, 2100 Copenhagen, Denmark; ² Department of Clinical Biochemistry, Copenhagen University Hospital, 2100 Copenhagen, Denmark; ³ Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark; ⁴ Institute for Experimental Medical Science, BMCI13, Lund University, 22184 Lund, Sweden; ⁵ Hematopoietic Stem Cell Laboratory, Lund Strategic Research Centre for Stem Cell Biology and Therapy, Lund University, 22184 Lund, Sweden; ⁶ European Molecular Biology Laboratory (EMBL) Mouse Biology Unit, 00015 Monterotondo, Italy

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.

[Keywords: Hematopoietic stem and progenitor cells; T-cell development; nonsense-mediated mRNA decay; programmed DNA rearrangements; alternative splicing; pseudogenes]

Received December 21, 2007; revised version accepted March 20, 2008.

E-MAIL porse{at}rh.dk; FAX 45-3532-5669.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.468808.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?