The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published online 11 September 2006 doi:10.1084/jem.20061020
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 10, 2239-2245
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BRIEF DEFINITIVE REPORT

 The requirement for Notch signaling at the ß-selection checkpoint in vivo is absolute and independent of the pre–T cell receptor

Ivan Maillard1,2, LiLi Tu2,3,4, Arivazhagan Sambandam3, Yumi Yashiro-Ohtani2,3,4, John Millholland2,3,4, Karen Keeshan2,3,4, Olga Shestova2,3,4, Lanwei Xu2,3,4, Avinash Bhandoola3, and Warren S. Pear2,3,4

1 Division of Hematology-Oncology, 2 Abramson Family Cancer Research Institute, 3 Department of Pathology and Laboratory Medicine, and 4 Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104

CORRESPONDENCE Warren S. Pear: wpear{at}mail.med.upenn.edu

Genetic inactivation of Notch signaling in CD4–CD8– double-negative (DN) thymocytes was previously shown to impair T cell receptor (TCR) gene rearrangement and to cause a partial block in CD4+CD8+ double-positive (DP) thymocyte development in mice. In contrast, in vitro cultures suggested that Notch was absolutely required for the generation of DP thymocytes independent of pre-TCR expression and activity. To resolve the respective role of Notch and the pre-TCR, we inhibited Notch-mediated transcriptional activation in vivo with a green fluorescent protein–tagged dominant-negative Mastermind-like 1 (DNMAML) that allowed us to track single cells incapable of Notch signaling. DNMAML expression in DN cells led to decreased production of DP thymocytes but only to a modest decrease in intracellular TCRß expression. DNMAML attenuated the pre-TCR–associated increase in cell size and CD27 expression. TCRß or TCR{alpha}ß transgenes failed to rescue DNMAML-related defects. Intrathymic injections of DNMAML– or DNMAML+ DN thymocytes revealed a complete DN/DP transition block, with production of DNMAML+ DP thymocytes only from cells undergoing late Notch inactivation. These findings indicate that the Notch requirement during the ß-selection checkpoint in vivo is absolute and independent of the pre-TCR, and it depends on transcriptional activation by Notch via the CSL/RBP-J–MAML complex.

I. Maillard and L. Tu contributed equally to this work.


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