| First Author | Frischmeyer-Guerrerio PA | Year | 2011 |
| Journal | Proc Natl Acad Sci U S A | Volume | 108 |
| Issue | 26 | Pages | 10638-43 |
| PubMed ID | 21670277 | Mgi Jnum | J:173551 |
| Mgi Id | MGI:5014443 | Doi | 10.1073/pnas.1019352108 |
| Citation | Frischmeyer-Guerrerio PA, et al. (2011) Perturbation of thymocyte development in nonsense-mediated decay (NMD)-deficient mice. Proc Natl Acad Sci U S A 108(26):10638-43 |
| abstractText | 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 Vbeta-to-DbetaJbeta rearrangements, whereas Dbeta-to-Jbeta 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. |
