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

Weischenfeldt, Joachim ; Damgaard, Inge ; Bryder, David LU ; Theilgaard-Moench, Kim ; Thorén, Lina LU ; Nielsen, Finn Cilius ; Jacobsen, Sten Eirik W LU ; Nerlov, Claus LU and Porse, Bo Torben (2008) In Genes & Development 22(10). p.1381-1396
Abstract
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... (More)
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. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
alternative splicing, programmed DNA rearrangements, T-cell development, nonsense-mediated mRNA decay, hematopoietic stem and progenitor cells, pseudogenes
in
Genes & Development
volume
22
issue
10
pages
1381 - 1396
publisher
Cold Spring Harbor Laboratory Press (CSHL)
external identifiers
  • wos:000255904500013
  • scopus:44149104364
  • pmid:18483223
ISSN
1549-5477
DOI
10.1101/gad.468808
language
English
LU publication?
yes
id
1ebde29f-e810-4c54-93ed-1b81c6afa5cd (old id 1203388)
date added to LUP
2016-04-01 14:55:58
date last changed
2022-08-29 18:29:11
@article{1ebde29f-e810-4c54-93ed-1b81c6afa5cd,
  abstract     = {{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.}},
  author       = {{Weischenfeldt, Joachim and Damgaard, Inge and Bryder, David and Theilgaard-Moench, Kim and Thorén, Lina and Nielsen, Finn Cilius and Jacobsen, Sten Eirik W and Nerlov, Claus and Porse, Bo Torben}},
  issn         = {{1549-5477}},
  keywords     = {{alternative splicing; programmed DNA rearrangements; T-cell development; nonsense-mediated mRNA decay; hematopoietic stem and progenitor cells; pseudogenes}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{1381--1396}},
  publisher    = {{Cold Spring Harbor Laboratory Press (CSHL)}},
  series       = {{Genes & Development}},
  title        = {{NMD is essential for hematopoietic stem and progenitor cells and for eliminating by-products of programmed DNA rearrangements}},
  url          = {{http://dx.doi.org/10.1101/gad.468808}},
  doi          = {{10.1101/gad.468808}},
  volume       = {{22}},
  year         = {{2008}},
}