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Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment

Thymic T cell lineage commitment is dependent on Notch1 (N1) receptor–mediated signaling. Although the physiological ligands that interact with N1 expressed on thymic precursors are currently unknown, in vitro culture systems point to Delta-like 1 (DL1) and DL4 as prime candidates. Using DL1- and DL...

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Autores principales: Koch, Ute, Fiorini, Emma, Benedito, Rui, Besseyrias, Valerie, Schuster-Gossler, Karin, Pierres, Michel, Manley, Nancy R., Duarte, Antonio, MacDonald, H. Robson, Radtke, Freddy
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2571927/
https://www.ncbi.nlm.nih.gov/pubmed/18824585
http://dx.doi.org/10.1084/jem.20080829
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author Koch, Ute
Fiorini, Emma
Benedito, Rui
Besseyrias, Valerie
Schuster-Gossler, Karin
Pierres, Michel
Manley, Nancy R.
Duarte, Antonio
MacDonald, H. Robson
Radtke, Freddy
author_facet Koch, Ute
Fiorini, Emma
Benedito, Rui
Besseyrias, Valerie
Schuster-Gossler, Karin
Pierres, Michel
Manley, Nancy R.
Duarte, Antonio
MacDonald, H. Robson
Radtke, Freddy
author_sort Koch, Ute
collection PubMed
description Thymic T cell lineage commitment is dependent on Notch1 (N1) receptor–mediated signaling. Although the physiological ligands that interact with N1 expressed on thymic precursors are currently unknown, in vitro culture systems point to Delta-like 1 (DL1) and DL4 as prime candidates. Using DL1- and DL4-lacZ reporter knock-in mice and novel monoclonal antibodies to DL1 and DL4, we show that DL4 is expressed on thymic epithelial cells (TECs), whereas DL1 is not detected. The function of DL4 was further explored in vivo by generating mice in which DL4 could be specifically inactivated in TECs or in hematopoietic progenitors. Although loss of DL4 in hematopoietic progenitors did not perturb thymus development, inactivation of DL4 in TECs led to a complete block in T cell development coupled with the ectopic appearance of immature B cells in the thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional N1 mutant mice. Collectively, our results demonstrate that DL4 is the essential and nonredundant N1 ligand responsible for T cell lineage commitment. Moreover, they strongly suggest that N1-expressing thymic progenitors interact with DL4-expressing TECs to suppress B lineage potential and to induce the first steps of intrathymic T cell development.
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spelling pubmed-25719272009-04-27 Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment Koch, Ute Fiorini, Emma Benedito, Rui Besseyrias, Valerie Schuster-Gossler, Karin Pierres, Michel Manley, Nancy R. Duarte, Antonio MacDonald, H. Robson Radtke, Freddy J Exp Med Brief Definitive Reports Thymic T cell lineage commitment is dependent on Notch1 (N1) receptor–mediated signaling. Although the physiological ligands that interact with N1 expressed on thymic precursors are currently unknown, in vitro culture systems point to Delta-like 1 (DL1) and DL4 as prime candidates. Using DL1- and DL4-lacZ reporter knock-in mice and novel monoclonal antibodies to DL1 and DL4, we show that DL4 is expressed on thymic epithelial cells (TECs), whereas DL1 is not detected. The function of DL4 was further explored in vivo by generating mice in which DL4 could be specifically inactivated in TECs or in hematopoietic progenitors. Although loss of DL4 in hematopoietic progenitors did not perturb thymus development, inactivation of DL4 in TECs led to a complete block in T cell development coupled with the ectopic appearance of immature B cells in the thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional N1 mutant mice. Collectively, our results demonstrate that DL4 is the essential and nonredundant N1 ligand responsible for T cell lineage commitment. Moreover, they strongly suggest that N1-expressing thymic progenitors interact with DL4-expressing TECs to suppress B lineage potential and to induce the first steps of intrathymic T cell development. The Rockefeller University Press 2008-10-27 /pmc/articles/PMC2571927/ /pubmed/18824585 http://dx.doi.org/10.1084/jem.20080829 Text en © 2008 Koch et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Reports
Koch, Ute
Fiorini, Emma
Benedito, Rui
Besseyrias, Valerie
Schuster-Gossler, Karin
Pierres, Michel
Manley, Nancy R.
Duarte, Antonio
MacDonald, H. Robson
Radtke, Freddy
Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment
title Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment
title_full Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment
title_fullStr Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment
title_full_unstemmed Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment
title_short Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment
title_sort delta-like 4 is the essential, nonredundant ligand for notch1 during thymic t cell lineage commitment
topic Brief Definitive Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2571927/
https://www.ncbi.nlm.nih.gov/pubmed/18824585
http://dx.doi.org/10.1084/jem.20080829
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