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Published July 1, 2007 | public
Journal Article

Molecular Dissection of Prethymic Progenitor Entry into the T Lymphocyte Developmental Pathway


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.

Additional Information

© 2007 The American Association of Immunologists, Inc. Received for publication December 18, 2006. Accepted for publication April 16, 2007. We thank Drs. Mark Leid (Oregon State University) and Dorina Avram (Albany Medical College) for stimulating discussions about Bcl11b and for generously sharing data before publication; John Cortese (Georgia Tech Research Institute) for helpful advice on terminology; Mary Yui (California Institute of Technology) for providing independent, confirmatory RNA samples; Rochelle Diamond and Stephanie Adams (California Institute of Technology) for expert advice and help with flow cytometry; Scott Bloom (Institute for Systems Biology) for excellent sequencing; Rob Butler, Robin Condie, Natasha Bouey, and Ruben Bayon (California Institute of Technology) for excellent mouse care; and Shirley Pease and the Genetically Engineered Mouse Service staff (California Institute of Technology) for timed pregnant mice. 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.

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