Notch3 is dispensable for thymocyte β-selection and Notch1-induced T cell leukemogenesis.
Notch1 (N1) signaling induced by intrathymic Delta-like (DL) ligands is required for T cell lineage commitment as well as self-renewal during "β-selection" of TCRβ⁺CD4⁻CD8⁻ double negative 3 (DN3) T cell progenitors. However, over-expression of the N1 intracellular domain (ICN1) renders N1...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2011-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC3172312?pdf=render |
id |
doaj-48adf2dfd9d14d038d7d8159b68c0821 |
---|---|
record_format |
Article |
spelling |
doaj-48adf2dfd9d14d038d7d8159b68c08212020-11-25T01:49:03ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0169e2493710.1371/journal.pone.0024937Notch3 is dispensable for thymocyte β-selection and Notch1-induced T cell leukemogenesis.Sara SulimanJoanne TanKeli XuPhilaretos C KousisPaul E KowalskiGreg ChangSean E EganCynthia GuidosNotch1 (N1) signaling induced by intrathymic Delta-like (DL) ligands is required for T cell lineage commitment as well as self-renewal during "β-selection" of TCRβ⁺CD4⁻CD8⁻ double negative 3 (DN3) T cell progenitors. However, over-expression of the N1 intracellular domain (ICN1) renders N1 activation ligand-independent and drives leukemic transformation during β-selection. DN3 progenitors also express Notch3 (N3) mRNA, and over-expression of ligand-independent mutant N3 (ICN3) influences β-selection and drives T cell leukemogenesis. However, the importance of ligand-activated N3 in promoting β-selection and ICN1-induced T cell leukemogenesis has not been examined. To address these questions we generated mice lacking functional N3. We confirmed that DN3 progenitors express N3 protein using a N3-specific antibody. Surprisingly however, N3-deficient DN3 thymocytes were not defective in generating DP thymocytes under steady state conditions or in more stringent competition assays. To determine if N3 co-operates with N1 to regulate β-selection, we generated N1;N3 compound mutants. However, N3 deficiency did not exacerbate the competitive defect of N1⁺/⁻ DN3 progenitors, demonstrating that N3 does not compensate for limiting N1 during T cell development. Finally, N3 deficiency did not attenuate T cell leukemogenesis induced by conditional expression of ICN1 in DN3 thymocytes. Importantly, we showed that in contrast to N1, N3 has a low binding affinity for DL4, the most abundant intrathymic DL ligand. Thus, despite the profound effects of ectopic ligand-independent N3 activation on T cell development and leukemogenesis, physiologically activated N3 is dispensable for both processes, likely because N3 interacts poorly with intrathymic DL4.http://europepmc.org/articles/PMC3172312?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sara Suliman Joanne Tan Keli Xu Philaretos C Kousis Paul E Kowalski Greg Chang Sean E Egan Cynthia Guidos |
spellingShingle |
Sara Suliman Joanne Tan Keli Xu Philaretos C Kousis Paul E Kowalski Greg Chang Sean E Egan Cynthia Guidos Notch3 is dispensable for thymocyte β-selection and Notch1-induced T cell leukemogenesis. PLoS ONE |
author_facet |
Sara Suliman Joanne Tan Keli Xu Philaretos C Kousis Paul E Kowalski Greg Chang Sean E Egan Cynthia Guidos |
author_sort |
Sara Suliman |
title |
Notch3 is dispensable for thymocyte β-selection and Notch1-induced T cell leukemogenesis. |
title_short |
Notch3 is dispensable for thymocyte β-selection and Notch1-induced T cell leukemogenesis. |
title_full |
Notch3 is dispensable for thymocyte β-selection and Notch1-induced T cell leukemogenesis. |
title_fullStr |
Notch3 is dispensable for thymocyte β-selection and Notch1-induced T cell leukemogenesis. |
title_full_unstemmed |
Notch3 is dispensable for thymocyte β-selection and Notch1-induced T cell leukemogenesis. |
title_sort |
notch3 is dispensable for thymocyte β-selection and notch1-induced t cell leukemogenesis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2011-01-01 |
description |
Notch1 (N1) signaling induced by intrathymic Delta-like (DL) ligands is required for T cell lineage commitment as well as self-renewal during "β-selection" of TCRβ⁺CD4⁻CD8⁻ double negative 3 (DN3) T cell progenitors. However, over-expression of the N1 intracellular domain (ICN1) renders N1 activation ligand-independent and drives leukemic transformation during β-selection. DN3 progenitors also express Notch3 (N3) mRNA, and over-expression of ligand-independent mutant N3 (ICN3) influences β-selection and drives T cell leukemogenesis. However, the importance of ligand-activated N3 in promoting β-selection and ICN1-induced T cell leukemogenesis has not been examined. To address these questions we generated mice lacking functional N3. We confirmed that DN3 progenitors express N3 protein using a N3-specific antibody. Surprisingly however, N3-deficient DN3 thymocytes were not defective in generating DP thymocytes under steady state conditions or in more stringent competition assays. To determine if N3 co-operates with N1 to regulate β-selection, we generated N1;N3 compound mutants. However, N3 deficiency did not exacerbate the competitive defect of N1⁺/⁻ DN3 progenitors, demonstrating that N3 does not compensate for limiting N1 during T cell development. Finally, N3 deficiency did not attenuate T cell leukemogenesis induced by conditional expression of ICN1 in DN3 thymocytes. Importantly, we showed that in contrast to N1, N3 has a low binding affinity for DL4, the most abundant intrathymic DL ligand. Thus, despite the profound effects of ectopic ligand-independent N3 activation on T cell development and leukemogenesis, physiologically activated N3 is dispensable for both processes, likely because N3 interacts poorly with intrathymic DL4. |
url |
http://europepmc.org/articles/PMC3172312?pdf=render |
work_keys_str_mv |
AT sarasuliman notch3isdispensableforthymocytebselectionandnotch1inducedtcellleukemogenesis AT joannetan notch3isdispensableforthymocytebselectionandnotch1inducedtcellleukemogenesis AT kelixu notch3isdispensableforthymocytebselectionandnotch1inducedtcellleukemogenesis AT philaretosckousis notch3isdispensableforthymocytebselectionandnotch1inducedtcellleukemogenesis AT paulekowalski notch3isdispensableforthymocytebselectionandnotch1inducedtcellleukemogenesis AT gregchang notch3isdispensableforthymocytebselectionandnotch1inducedtcellleukemogenesis AT seaneegan notch3isdispensableforthymocytebselectionandnotch1inducedtcellleukemogenesis AT cynthiaguidos notch3isdispensableforthymocytebselectionandnotch1inducedtcellleukemogenesis |
_version_ |
1725009254167871488 |