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

作者：Frischmeyer Guerrerio Pamela A; Montgomery Robert A; Warren Daniel S; Cooke Sara K; Lutz Johannes; Sonnenday Christopher J; Guerrerio Anthony L; Dietz Harry C^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(26): 10638-10643.

DOI：10.1073/pnas.1019352108

• RNA
• T-cell receptor rearrangement
• allelic exclusion
• B-cell receptor rearrangement
• immune development

The random nature of T-cell receptor-beta (TCR-beta) 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-beta, and increased expression of CD25, suggesting a defect in pre-TCR signaling. Transgenic fetal thymocytes also demonstrated diminished endogenous V beta-to-D beta J beta rearrangements, whereas D beta-to-J beta rearrangements were unperturbed, suggesting that inhibition of NMD induces premature shut-off of TCR-beta rearrangement. Developmental arrest of thymocytes is prevented by the introduction of a fully rearranged TCR-beta 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.

• 出版日期2011-6-28