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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
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
external identifiers
  • wos:000255904500013
  • scopus:44149104364
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
2008-09-16 15:54:37
date last changed
2017-10-01 04:30:26
@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},
  keyword      = {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},
  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},
  volume       = {22},
  year         = {2008},
}