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Division of Biology, California Institute of Technology, Pasadena, CA 91125
Notch signaling activates T lineage differentiation from hemopoietic progenitors, but relatively few regulators that initiate this program have been identified, e.g., GATA3 and T cell factor-1 (TCF-1) (gene name Tcf7). To identify additional regulators of T cell specification, a cDNA library from mouse Pro-T cells was screened for genes that are specifically up-regulated in intrathymic T cell precursors as compared with myeloid progenitors. Over 90 genes of interest were identified, and 35 of 44 tested were confirmed to be more highly expressed in T lineage precursors relative to precursors of B and/or myeloid lineage. To a remarkable extent, however, expression of these T lineage-enriched genes, including zinc finger transcription factor, helicase, and signaling adaptor genes, was also shared by stem cells (Lin–Sca-1+Kit+CD27–) and multipotent progenitors (Lin–Sca-1+Kit+CD27+), although down-regulated in other lineages. Thus, a major fraction of these early T lineage genes are a regulatory legacy from stem cells. The few genes sharply up-regulated between multipotent progenitors and Pro-T cell stages included those encoding transcription factors Bcl11b, TCF-1 (Tcf7), and HEBalt, Notch target Deltex1, Deltex3L, Fkbp5, Eva1, and Tmem131. Like GATA3 and Deltex1, Bcl11b, Fkbp5, and Eva1 were dependent on Notch/Delta signaling for induction in fetal liver precursors, but only Bcl11b and HEBalt were up-regulated between the first two stages of intrathymic T cell development (double negative 1 and double negative 2) corresponding to T lineage specification. Bcl11b was uniquely T lineage restricted and induced by Notch/Delta signaling specifically upon entry into the T lineage differentiation pathway.
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.
1 This work was supported by grants (to E.V.R.) from the National Science Foundation (MCB-9983129) and National Institutes of Health U.S. Public Health Service (R01 CA90233 and R01 CA98925), by National Institutes of Health U.S. Public Health Service awards K08 AI054699 (to C.C.T.) and F32 AI068366 (to J.E.M.); and from the DNA Sequencer Royalty Fund at the California Institute of Technology.
2 C.C.T. and E.-S.D.-F. contributed equally to this study.
3 Current address: Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87544.
4 Current address: Institute for Systems Biology, Seattle, WA 98103.
5 Current address: Department of Clinical Chemistry, Microbiology and Immunology, University Hospital Ghent, Ghent University, Ghent, Belgium.
6 Address correspondence and reprint requests to Dr. Ellen V. Rothenberg, Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125. E-mail address: evroth{at}its.caltech.edu
7 Abbreviations used in this paper: BM, bone marrow; DN, double negative; Dtx3L, Deltex3-like; pT
, pre-TCR; qRT-PCR, quantitative real-time PCR; TCF-1, T cell factor-1.
8 The online version of this article contains supplemental material.
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