Wang, Hua and Diamond, Rochelle A. and Rothenberg, Ellen V. (1998) Cross-lineage expression of Ig-beta (B29) in thymocytes: Positive and negative gene regulation to establish T cell identity. Proceedings of the National Academy of Sciences of the United States of America, 95 (12). pp. 6831-6836. ISSN 0027-8424 http://resolver.caltech.edu/CaltechAUTHORS:WANpnas98
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Developmental commitment involves activation of lineage-specific genes, stabilization of a lineage-specific gene expression program, and permanent inhibition of inappropriate characteristics. To determine how these processes are coordinated in early T cell development, the expression of T and B lineage-specific genes was assessed in staged subsets of immature thymocytes. T lineage characteristics are acquired sequentially, with germ-line T cell antigen receptor-beta transcripts detected very early, followed by CD3 epsilon and terminal deoxynucleotidyl transferase, then pT alpha, and finally RAG1. Only RAG1 expression coincides with commitment. Thus, much T lineage gene expression precedes commitment and does not depend on it. Early in the course of commitment to the T lineage, thymocytes lose the ability to develop into B cells. To understand how this occurs, we also examined expression of well defined B lineage-specific genes. Although lambda 5 and Ig-alpha are not expressed, the mu(0) and I mu transcripts from the unrearranged IgH locus are expressed early, in distinct patterns, then repressed just before RAG1 expression. By contrast, RNA encoding the B cell receptor component Ig-beta was found to be transcribed in all immature thymocyte subpopulations and throughout most thymocyte differentiation. Ig-beta expression is down-regulated only during positive selection of CD4(+)CD8(-) cells. Thus several key participants in the B cell developmental program are expressed in non-B lineage-committed cells, and one is maintained even through commitment to an alternative lineage, and repressed only after extensive T lineage differentiation. The results show that transcriptional activation of "lymphocyte-specific" genes can occur in uncommitted precursors, and that T lineage commitment is a composite of distinct positive and negative regulatory events.
|Additional Information:||Copyright © 1998 by the National Academy of Sciences. Communicated by Ray D. Owen, California Institute of Technology, Pasadena, CA, April 8, 1998 (received for review November 25, 1997). We are very grateful to Patrick Koen for excellent assistance with the flow cytometry, to Ray Hotz for essential care and management of the mutant mice, and to members of the Rothenberg lab and the Stowers Consortium at the California Institute of Technology for helpful and stimulating discussions. This work was supported by a grant from the U.S. Public Health Service (RO1 AI34041), by a grant from the State of California Tobacco-Related Disease Research Program (4RT 0264), and by funding from the Stowers Institute for Medical Research. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.|
|Subject Keywords:||natural-killer-cells, murine bone-marrow, fetal liver, precursor cells, receptor gene, B-cells, differentiation, transcription, progenitors, thymus|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Tony Diaz|
|Deposited On:||15 Nov 2005|
|Last Modified:||26 Dec 2012 08:42|
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