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The Basic Helix-Loop-Helix Transcription Factor HEBAlt Is Expressed in Pro-T Cells and Enhances the Generation of T Cell Precursors

Wang, Duncheng and Claus, Carol L. and Vaccarelli, Giovanna and Braunstein, Marsela and Schmitt, Thomas M. and Zúñiga-Pflücker, Juan Carlos and Rothenberg, Ellen V. and Anderson, Michele K. (2006) The Basic Helix-Loop-Helix Transcription Factor HEBAlt Is Expressed in Pro-T Cells and Enhances the Generation of T Cell Precursors. Journal of Immunology, 177 (1). pp. 109-119. ISSN 0022-1767.

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The basic helix-loop-helix (bHLH) transcription factors HEB and E2A are critical mediators of gene regulation during lymphocyte development. We have cloned a new transcription factor, called HEBAlt, from a pro-T cell cDNA library. HEBAlt is generated by alternative transcriptional initiation and splicing from the HEB gene locus, which also encodes the previously characterized E box protein HEBCan. HEBAlt contains a unique N-terminal coding exon (the Alt domain) that replaces the first transactivation domain of HEBCan. Downstream of the Alt domain, HEBAlt is identical to HEBCan, including the DNA binding domain. HEBAlt is induced in early thymocyte precursors and down-regulated permanently at the double negative to double positive (DP) transition, whereas HEBCan mRNA expression peaks at the DP stage of thymocyte development. HEBAlt mRNA is up-regulated synergistically by a combination of HEBCan activity and Delta-Notch signaling. Retroviral transduction of HEBAlt or HEBCan into hemopoietic stem cells followed by OP9-DL1 coculture revealed that HEBAlt-transduced precursors generated more early T lineage precursors and more DP pre-T cells than control transduced cells. By contrast, HEBCan-transduced cells that maintained high level expression of the HEBCan transgene were inhibited in expansion and progression through T cell development. HEB−/− fetal liver precursors transduced with HEBAlt were rescued from delayed T cell specification, but HEBCan-transduced HEB−/− precursors were not. Therefore, HEBAlt and HEBCan are functionally distinct transcription factors, and HEBAlt is specifically required for the efficient generation of early T cell precursors.

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Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2006 The American Association of Immunologists. Received June 21, 2005. Accepted April 12, 2006. We thank Rochelle Diamond for expert advice and execution in cell sorting and other aspects of this study, and Chris Dionne and Kevin Tse for the adh.2C2 cell line. We are indebted to Trang Hoang for providing the HEB+/− mice used for timed matings in this study and to Yuan Zhuang for permission to use them. We thank past members of the Rothenberg lab for helpful discussion and sharing of unpublished results including Hua Wang, Gabriela Hernández-Hoyos, Janice Telfer, Elizabeth-Sharon David, Rashmi Pant, and Tom Taghon. We thank Renee de Pooter and Maria Ciofani for help with the OP9-DL1 coculture system, Gisele Knowles for expert cell sorting at Sunnybrook Research Institute (SRI), and the staff of the Comparative Research Facility at SRI for animal care. We also acknowledge Trista Steele and Pier-Andrée Penttila for timely provision of Abs from the SRI Ab Facility, and Edwin Chen for help with the gel shift assays and Western blots. Thanks to Cynthia Guidos for critical reading of the manuscript, and to Jonathan Rast for providing technical advice, reagents, and insights. The authors have no financial conflict of interest. This work was supported by Grant MOP64185 from Canadian Institutes of Health Research (to M.K.A.), by Grant R01 CA90233 from the National Institutes of Health (to E.V.R.), the Sunnybrook Research Institute, and the Stowers Institute for Medical Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Canadian Institutes of Health ResearchMOP64185
NIHR01 CA90233
Sunnybrook Research InstituteUNSPECIFIED
Stowers Institute for Medical ResearchUNSPECIFIED
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Record Number:CaltechAUTHORS:20170206-105418120
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Official Citation:The Basic Helix-Loop-Helix Transcription Factor HEBAlt Is Expressed in Pro-T Cells and Enhances the Generation of T Cell Precursors Duncheng Wang, Carol L. Claus, Giovanna Vaccarelli, Marsela Braunstein, Thomas M. Schmitt, Juan Carlos Zúñiga-Pflücker, Ellen V. Rothenberg, Michele K. Anderson The Journal of Immunology July 1, 2006, 177 (1) 109-119; DOI: 10.4049/jimmunol.177.1.109
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74074
Deposited By: Tony Diaz
Deposited On:06 Feb 2017 20:31
Last Modified:27 Apr 2020 23:12

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