HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Related articles in The JI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Höflinger, S. Articles by Busslinger, M. Search for Related Content PubMed PubMed Citation Articles by Höflinger, S. Articles by Busslinger, M.

Analysis of Notch1 Function by In Vitro T Cell Differentiation of Pax5 Mutant Lymphoid Progenitors¹

Sonja Höflinger^2,*, Kamala Kesavan^2,*, Martin Fuxa^*, Caroline Hutter^*, Barry Heavey^3,*, Freddy Radtke and Meinrad Busslinger^4,*

^* Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria; and Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland

Signaling through the Notch1 receptor is essential for T cell development in the thymus. Stromal OP9 cells ectopically expressing the Notch ligand Delta-like1 mimic the thymic environment by inducing hemopoietic stem cells to undergo in vitro T cell development. Notch1 is also expressed on Pax5^–/– pro-B cells, which are clonable lymphoid progenitors with a latent myeloid potential. In this study, we demonstrate that Pax5^–/– progenitors efficiently differentiate in vitro into CD4⁺CD8⁺ and T cells upon coculture with OP9-Delta-like1 cells. In vitro T cell development of Pax5^–/– progenitors strictly depends on Notch1 function and progresses through normal developmental stages by expressing T cell markers and rearranging TCR, , and loci in the correct temporal sequence. Notch-stimulated Pax5^–/– progenitors efficiently down-regulate the expression of B cell-specific genes, consistent with a role of Notch1 in preventing B lymphopoiesis in the thymus. At the same time, Notch signaling rapidly induces cell surface expression of the c-Kit receptor and transcription of the target genes Deltex1 and pre-T concomitant with the activation of TCR V germline transcription and the regulatory genes GATA3 and Tcf1. These data suggest that Notch1 acts upstream of GATA3 and Tcf1 in early T cell development and regulates V-DJ rearrangements by controlling the chromatin accessibility of V genes at the TCR locus.

Related articles in The JI:

IN THIS ISSUE

The JI 2004 173: 3579-3580. [Full Text]  

This article has been cited by other articles:

				U. Koch, E. Fiorini, R. Benedito, V. Besseyrias, K. Schuster-Gossler, M. Pierres, N. R. Manley, A. Duarte, H. R. MacDonald, and F. Radtke Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment J. Exp. Med., September 29, 2008; (2008) jem.20080829. [Abstract] [Full Text] [PDF]

				C. C. Tydell, E.-S. David-Fung, J. E. Moore, L. Rowen, T. Taghon, and E. V. Rothenberg Molecular Dissection of Prethymic Progenitor Entry into the T Lymphocyte Developmental Pathway J. Immunol., July 1, 2007; 179(1): 421 - 438. [Abstract] [Full Text] [PDF]

				B. A. Schwarz, A. Sambandam, I. Maillard, B. C. Harman, P. E. Love, and A. Bhandoola Selective Thymus Settling Regulated by Cytokine and Chemokine Receptors J. Immunol., February 15, 2007; 178(4): 2008 - 2017. [Abstract] [Full Text] [PDF]

				A. Souabni, W. Jochum, and M. Busslinger Oncogenic role of Pax5 in the T-lymphoid lineage upon ectopic expression from the immunoglobulin heavy-chain locus Blood, January 1, 2007; 109(1): 281 - 289. [Abstract] [Full Text] [PDF]

				A. Krueger, A. I. Garbe, and H. von Boehmer Phenotypic plasticity of T cell progenitors upon exposure to Notch ligands J. Exp. Med., August 7, 2006; 203(8): 1977 - 1984. [Abstract] [Full Text] [PDF]

				T. Ikawa, H. Kawamoto, A. W. Goldrath, and C. Murre E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment J. Exp. Med., May 15, 2006; 203(5): 1329 - 1342. [Abstract] [Full Text] [PDF]

				M. Mohtashami and J. C. Zuniga-Pflucker Cutting Edge: Three-Dimensional Architecture of the Thymus Is Required to Maintain Delta-Like Expression Necessary for Inducing T Cell Development J. Immunol., January 15, 2006; 176(2): 730 - 734. [Abstract] [Full Text] [PDF]

				E. M. K. Smith, P. Akerblad, T. Kadesch, H. Axelson, and M. Sigvardsson Inhibition of EBF function by active Notch signaling reveals a novel regulatory pathway in early B-cell development Blood, September 15, 2005; 106(6): 1995 - 2001. [Abstract] [Full Text] [PDF]

				T. N. Taghon, E.-S. David, J. C. Zuniga-Pflucker, and E. V. Rothenberg Delayed, asynchronous, and reversible T-lineage specification induced by Notch/Delta signaling Genes & Dev., April 15, 2005; 19(8): 965 - 978. [Abstract] [Full Text] [PDF]