TY - JOUR
T1 - Perturbation of thymocyte development in nonsense-mediated decay (NMD)-deficient mice
AU - Frischmeyer-Guerrerio, Pamela A.
AU - Montgomery, Robert A.
AU - Warren, Daniel S.
AU - Cooke, Sara K.
AU - Lutz, Johannes
AU - Sonnenday, Christopher J.
AU - Guerrerio, Anthony L.
AU - Dietz, Harry C.
PY - 2011/6/28
Y1 - 2011/6/28
N2 - 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.
AB - 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.
KW - Allelic exclusion
KW - B-cell receptor rearrangement
KW - Immune development
KW - RNA
KW - T-cell receptor rearrangement
UR - http://www.scopus.com/inward/record.url?scp=79960612825&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960612825&partnerID=8YFLogxK
U2 - 10.1073/pnas.1019352108
DO - 10.1073/pnas.1019352108
M3 - Article
C2 - 21670277
AN - SCOPUS:79960612825
SN - 0027-8424
VL - 108
SP - 10638
EP - 10643
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -