Perturbation of thymocyte development in nonsense-mediated decay (NMD)-deficient mice.
Proc Natl Acad Sci U S A
; 108(26): 10638-43, 2011 Jun 28.
Article
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| MEDLINE
| ID: mdl-21670277
ABSTRACT
The random nature of T-cell receptor-ß (TCR-ß) 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-ß, and increased expression of CD25, suggesting a defect in pre-TCR signaling. Transgenic fetal thymocytes also demonstrated diminished endogenous Vß-to-DßJß rearrangements, whereas Dß-to-Jß rearrangements were unperturbed, suggesting that inhibition of NMD induces premature shut-off of TCR-ß rearrangement. Developmental arrest of thymocytes is prevented by the introduction of a fully rearranged TCR-ß 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.
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Bases de datos:
MEDLINE
Asunto principal:
Timo
/
ARN Mensajero
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos