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

Pamela A. Frischmeyer-Guerrerio, Robert A. Montgomery, Daniel S. Warren, Sara K. Cooke, Johannes Lutz, Christopher J. Sonnenday, Anthony L. Guerrerio, Harry C. Dietz

Research output: Contribution to journalArticle

Abstract

The random nature of T-cell receptor-β (TCR-β) recombination needed to generate immunological diversity dictates that twothirds 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.

Original languageEnglish (US)
Pages (from-to)10638-10643
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number26
DOIs
StatePublished - Jun 28 2011

Keywords

  • Allelic exclusion
  • B-cell receptor rearrangement
  • Immune development
  • RNA
  • T-cell receptor rearrangement

ASJC Scopus subject areas

  • General

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