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Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10638-43. doi: 10.1073/pnas.1019352108. Epub 2011 Jun 13.

Perturbation of thymocyte development in nonsense-mediated decay (NMD)-deficient mice.

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  • 1Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract

The random nature of T-cell receptor-β (TCR-β) recombination needed to generate immunological diversity dictates that two-thirds of alleles will be out-of-frame. Transcripts derived from nonproductive rearrangements are cleared by the nonsense-mediated mRNA decay (NMD) pathway, the process by which cells selectively degrade transcripts harboring premature termination codons. Here, we demonstrate that the fetal thymus in transgenic mice that ubiquitously express a dominant-negative form of Rent1/hUpf1, an essential trans-effector of NMD, shows decreased cell number, reduced CD4CD8 double-positive thymocytes, diminished expression of TCR-β, and increased expression of CD25, suggesting a defect in pre-TCR signaling. Transgenic fetal thymocytes also demonstrated diminished endogenous Vβ-to-DβJβ rearrangements, whereas Dβ-to-Jβ rearrangements were unperturbed, suggesting that inhibition of NMD induces premature shut-off of TCR-β rearrangement. Developmental arrest of thymocytes is prevented by the introduction of a fully rearranged TCR-β transgene that precludes generation of out-of-frame transcripts, suggesting direct mRNA-mediated trans-dominant effects. These data document that NMD has been functionally incorporated into developmental programs during eukaryotic evolution.

PMID:
21670277
[PubMed - indexed for MEDLINE]
PMCID:
PMC3127929
Free PMC Article
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