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

Författare:
Publiceringsår: 2008
Språk: Engelska
Sidor: 1381-1396
Publikation/Tidskrift/Serie: Genes & Development
Volym: 22
Nummer: 10
Dokumenttyp: Artikel
Förlag: Cold Spring Harbor Laboratory Press

Sammanfattning

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.

Disputation

Nyckelord

  • Medicine and Health Sciences
  • alternative splicing
  • programmed DNA rearrangements
  • T-cell development
  • nonsense-mediated mRNA decay
  • hematopoietic stem and progenitor cells
  • pseudogenes

Övriga

Published
Yes
  • ISSN: 0890-9369

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